Humans maintain a relatively constant core temperature through the dynamic balance between endogenous heat production and heat dissipation to the surrounding environment. In response to metabolic or environmental disturbances to heat balance, the autonomic nervous system initiates cutaneous vasodilation and eccrine sweating to facilitate higher rates of dry (primarily convection and radiation) and evaporative transfer from the body surface; however, absolute heat losses are ultimately governed by the properties of the skin and the environment. Over the duration of a heat exposure, the cumulative imbalance between heat production and heat dissipation leads to body heat storage, but the consequent change in core temperature, which has implications for health and safety in occupational and athletic settings particularly among certain clinical populations, involves a complex interaction between changes in body heat content and the body’s morphological characteristics (mass, surface area, and tissue composition) that collectively determine the body’s thermal inertia. The aim of this review is to highlight the biophysical aspects of human core temperature regulation by outlining the principles of human energy exchange and examining the influence of body morphology during exercise and environmental heat stress. An understanding of the biophysical factors influencing core temperature will enable researchers and practitioners to better identify and treat individuals/populations most vulnerable to heat illness and injury during exercise and extreme heat events. Further, appropriate guidelines may be developed to optimize health, safety, and work performance during heat stress.