The independent effects of acute heat and hypoxic stress on human physiological function and performance are relatively well documented. Although in the field these environmental stressors rarely occur in isolation the effects of combined or sequential exposure to them has not been extensively studied in humans. Animal models have however shown that acclimation to one stressor can induce ‘cross acclimation’ a positive adaptive response upon exposure to a different stressor. The three studies within this thesis were conducted in humans to assess how exposure to acute and repeated exposures to heat affects the later physiological and cellular responses to acute exercise in normobaric hypoxia. A possible site for any cross-acclimatory affects and conferred cellular tolerance resides in the heat shock response (HSR) and the increased expression of heat shock proteins (HSPs). The 72 kilodalton HSP, HSP72 has been implicated in heat acclimation mediated cross acclimation in rodent models, and also shown to be important in the human adaptation to heat and hypoxic stressors. Study One determined the physiological and HSR to exercise in both heat (HEAT; 40°C) and hypoxia (HYP; FIO2 0.14) alone, and in combination (COM) as well as a normothermic normoxic control (NORM). 24 hours after the initial exposure a hypoxic stress test (HST; 15 minutes of seated rest and 60 minutes of cycling exercise at 50% normoxic peak) was conducted to determine what effect the prior stress exposure had on both whole body physiological responses and the cellular HSR. It was hypothesised that the stressor that elicited the greatest physiological strain and HSR on day one would have the biggest effect on reducing physiological strain in a subsequent HST. Twelve male participants completed 4 trials consisting of a 15 minute rest period in normoxic temperate conditions, followed by 30 minutes seated rest and 90 minutes cycling exercise at 50% Npeak within NORM, HEAT, HYP and COM. 24 hours after completing this exercise bout, participants undertook a HST. Exercise duration was reduced in HEAT (78 ± 12mins), HYP (81 ± 13mins) and the CON (73 ± 19mins) trial compared to the NORM (89 ± 3mins). HR and core body temperature (Tcore), and thus physiological strain, were greater in the HEAT and COM trial compared to HYP alone. This response was also observed with post exercise monocyte HSP72 (mHSP72). Basal HSP72 was elevated 24 hours after the HEAT and COM and attenuated post HST. Exercising HR, Tcore and PSI was reduced during the HST 24 hours after a heat stressor had been applied, but unaffected by a prior hypoxic exposure. Therefore the hypothesis was accepted. It was concluded that at the temperature and level of hypoxia studied, a prior exposure to exercise heat stress was beneficial when conducting subsequent acute hypoxic exercise. Study Two investigated the effect of short-term heat acclimation (STHA) on subsequent hypoxic tolerance in 16 male participants divided equally into 2 matched groups. This study also examined the response of extracellular HSP72 (eHSP72) to acute hypoxic exercise. It was hypothesized that STHA would increase basal HSP72 and that the post HST increase in HSP72 would be attenuated in this group, indicating conferred cellular tolerance. Eight males completed a HST one week before undertaking 3 consecutive days of STHA (60 min/day, 40°C, 50%peak) followed by a final HST 48-hours after the last acclimation day. The matched controls (CON) completed an identical protocol in normothermic, normoxic conditions. The initial HST induced a post exercise increase in HSP72 in both groups. HSP72 was increased after the first day of heat acclimation and unchanged in the control group. After acclimation day 2, basal HSP72 was increased from on day 1 basal values and the post exercise increase observed on day 1 was absent in the heat group. The increase in basal HSP72 persisted until the post acclimation HST for the STHA group and post exercise HSP72 was attenuated. eHSP72 increased immediately after the HST in both groups, however large inter-individual variation was evident. Mean exercising HR, Tcore and physiological strain was reduced during the HST in the STHA group, indicating that a short period of heat acclimation can improve both cellular and physiological tolerance to exercise in acute normobaric hypoxia. Study Three examined how a prior period of long term heat acclimation (LTHA) or time and absolute exercise intensity matched hypoxic acclimation (HA) affects both tolerance and performance to a HST and 16.1 km time trial (TT). Plasma hypoxia inducible 1 alpha (HIF-1α) was assessed before and after the acclimation periods as this transcription factor plays an important role in heat acclimation mediated cross tolerance. Twenty-one male participants completed ten 60-minute cycling bouts (50% Npeak) in thermoneutral, normoxic conditions (CON, 18°C, FIO2 0.209; n = 7), heated conditions (LTHA, 40°C, n = 7) or hypoxic conditions (HA, FIO2 0.14, n = 7). A HST immediately followed by a 16.1 km TT was completed one week before and 48 hours after the acclimation period. Both LTHA and HA induced increases in basal HSP72 by the end of the 10-day period. Increases in basal HSP72 occurred earlier in the acclimation period and to a greater magnitude with LTHA. Prior to the post acclimation HST both basal HSP72 and plasma HIF1-α were elevated in the LTHA and HA groups, with no changes observed in CON compared to the initial HST. Post HST mHSP72 and HIF1-α was attenuated in LTHA and HA. Mean exercising HR, Tcore and PSI were reduced in the LTHA group with no changes in these physiological variables observed in the HA or CON groups. During the TT, mean power output (MPO) was elevated at each kilometer in the HA group, leading to an improved performance after acclimation. The LTHA group produced greater power outputs between km 1 – 8 and 14-16 and consequently were faster overall compared to their pre acclimation TT. This indicates an altered pacing strategy following the LTHA period. The data suggests that, at the levels studied herein, LTHA induces a faster accumulation of basal mHSP72 over a 10-day period, occurring to a greater magnitude. This is the first study to examine the plasma HIF-1α response to both heat and hypoxic acclimation in humans. The data suggest that each environmental stressor induces an increase in resting levels of this transcription factor, however further study is required due to the large variation in response. It is not yet known whether the benefits conferred from heat to acute bouts of hypoxia would translate to more prolonged hypoxic exposures. Both the mechanisms of cross-acclimation and the effects of extended or prolonged hypoxic exposure following heat acclimation require further study. The immediate post exercise mHSP72 increase to exercise was consistently shown to be greater following a heat stress condition when compared to hypoxia. STHA induced greater increases in basal mHSP72 compared to the acute exposure, further attenuating post HST mHSP72 elevations and physiological strain. LTHA increased basal mHSP72 at a faster rate and magnitude than HA and 16.1km time trial performance improved to a similar magnitude following both heat and hypoxic acclimation It is speculated that heat acclimation mediated activation of HIF-1α may hold a key mechanistic role in the observed cross-acclimatory response. From a practical perspective, the use of heat-stress based acclimation/training programs may provide a cheaper and more effective means of preparing individuals for subsequent hypoxic exposure. Future studies should confirm these observations hold true in a hypobaric environment and establish how prior heat acclimation may impact on longer term exposures and adaptations to hypoxic environments.