Purpose To review factors that impact the effect of hot environments on the human body in order to develop a conceptual model of human biological response. Methods The organizing concept for the model development was the multilevel integration of three major factors, exposure to heat, sensitivity and adaptive capacity, and the heat stress response. Exposure of a vulnerable occupational group was used to illustrate the components of the model. Findings Components of this framework include the hazard (environmental heat stress), vulnerability factors (workplace exposure, sensitivity and adaptive capacity), and the heat stress response. The combination of the vulnerability factors of workplace exposure (work intensity, duration), sensitivity (age, gender, etc.), and adaptive capacity (hydration, clothing, work hygiene) mediate a worker's heat stress response to the hazard. A worker's heat stress response can be classified as progressing towards two outcomes: physiologic equilibrium or physiologic disequilibrium. Conclusions This framework provides a starting point for the design and development of studies of heat‐related illness (HRI) in farmworker and other vulnerable populations exposed to rising global temperatures. Clinical Relevance Identification of vulnerability factors to HRI, informs research designs which will lead to the development of public health interventions.