In many occupational settings, clothing must be worn to protect individuals from hazards in their work environment. However, personal protective clothing (PPC) restricts heat exchange with the environment due to high thermal resistance and low water vapor permeability. As a consequence, individuals who wear PPC often work in uncompensable heat stress conditions where body heat storage continues to rise and the risk of heat injury is greatly enhanced. Tolerance time while wearing PPC is influenced by three factors: (i) initial core temperature (Tc), affected by heat acclimation, precooling, hydration, aerobic fitness, circadian rhythm, and menstrual cycle; (ii) Tc tolerated at exhaustion, influenced by state of encapsulation, hydration, and aerobic fitness; and (iii) the rate of increase in Tc from beginning to end of the heat-stress exposure, which is dependent on the clothing characteristics, thermal environment, work rate, and individual factors like body composition and economy of movement. Methods to reduce heat strain in PPC include increasing clothing permeability for air, adjusting pacing strategy, including work/rest schedules, physical training, and cooling interventions, although the additional weight and bulk of some personal cooling systems offset their intended advantage. Individuals with low body fatness who perform regular aerobic exercise have tolerance times in PPC that exceed those of their sedentary counterparts by as much as 100% due to lower resting Tc, the higher Tc tolerated at exhaustion and a slower increase in Tc during exercise. However, questions remain about the importance of activity levels, exercise intensity, cold water ingestion, and plasma volume expansion for thermotolerance.