These studies investigated 1) mechanisms underlying the well-established reduction in orthostatic tolerance (OT) that occurs in humans during heat stress (HS) relative to normothermia (NT) with particular focus on determining factors contributing to the high degree of inter-individual variability in this phenomenon; and 2) influence of obesity on OT, and mechanisms underlying reduced OT, should it exist. In Study #1, OT was assessed during lower body negative pressure (LBNP), and quantified with a cumulative stress index (CSI). Differences in CSI (CSIdiff) between thermal conditions were used to categorize individuals most (LargeDiff) and least (SmallDiff) affected by HS (P<0.001). Cerebral perfusion [indexed as middle cerebral artery blood velocity (MCA Vm̳̳e̳a̳n̳)] was reduced during HS compared to NT (P<0.001); however, the magnitude of reduction did not differ between groups (P=0.51). In the initial stage of LBNP during HS (LBNP20), MCA Vm̳̳e̳a̳n̳ and end-tidal CO₂ (PETC̳O̳₂) were reduced, and heart rate (HR) was higher in the LargeDiff group compared to SmallDiff group (all P<0.05); yet, mean arterial pressure was similar (P=0.23) suggesting impaired mechanisms regulating MCA Vm̳̳e̳a̳n̳ may affect OT. In Study #2, mechanisms of cerebrovascular control were compared in LargeDiff and SmallDiff individuals. Although estimates of cerebral autoregulation (CA) and cerebrovascular reactivity to CO₂ were improved and reduced respectively, during HS compared to NT (all P<0.05), no relationship existed between CA or cerebral reactivity to hypocapnia and CSIdiff (all P>0.05). In Study #3, OT was lower in obese compared to non-obese individuals (P<0.01), and BMI was negatively correlated with CSI (R = -0.47; P < 0.01). HR was elevated at rest and in every level of LBNP (all P<0.05) in obese; yet, peak HR during LBNP was similar between groups (P=0.90). MCA Vm̳̳e̳a̳n̳ and cerebral vascular conductance were similar at rest and during LBNP (both P>0.05), and CA was similar between groups (P>0.05). In summary, a high HR prior to-, and a high HR and reduced MCA Vm̳̳e̳a̳n̳ at the onset of an orthostatic challenge result in reduced OT during HS in healthy individuals; however, reduced OT in obese is related to a higher %peak HR at rest. / text