Cardiovascular disease is the leading cause of death in the developed world. The majority of cardiovascular diseases are characterized by disorders of the arteries, predominantly caused by endothelial dysfunction and arterial stiffening. Passive heat stress results in elevations in core temperature (inducing heat shock protein expression) and changes in cardiovascular hemodynamics, such as increased cardiac output and shear stress, that are similar to exercise. Thus, repeated passive heat stress (“heat therapy”) may provide an alternative means of improving cardiovascular health, particularly for patients with limited exercise tolerance and/or capabilities. Therefore, the goal of this dissertation was to perform integrative studies to determine the effects of heat therapy on vascular function and the associated cellular pathways in young, sedentary humans. Twenty subjects were assigned to participate in 8 weeks (4-5x/week) of heat therapy (N=10; immersion in a 40.5°C bath sufficient to maintain rectal temperature ≥38.5°C for 60 min/session) or thermoneutral water immersion (N=10; sham). As discussed in Chapter V, we found that heat therapy improved numerous well-established biomarkers of conduit vessel/macrovascular function, including flow-mediated dilation (a measure of endothelial function), arterial stiffness, intima media thickness, and blood pressure. Heat therapy also improved microvascular function, as discussed in Chapter VI, measured as improved cutaneous thermal hyperemia and nitric oxide-dependent dilation (the difference between microdialysis sites receiving Lactated Ringer’s [control] and nitric oxide synthase inhibition). No changes were observed in any variables in sham subjects. In Chapter VII, we showed that both direct cellular heating and serum collected from human subjects following heat therapy improved nitric oxide bioavailability and angiogenesis in cultured endothelial cells, providing potential mechanisms by which heat therapy improves vascular function in vivo. Therefore, the studies described herein provide comprehensive evidence that passive heat therapy improves vascular health and insight into the mechanisms involved. Our data presented in Chapters IV-VII, combined with pilot data we conducted in spinal cord injured individuals (Chapter VIII), strongly indicate that passive heat therapy could be used as a simple and effective tool to improve cardiovascular health in a variety of patient populations. This dissertation includes published and unpublished co-authored material.