Various and disparate technical disciplines have identified a growing need for tools to predict human thermal and thermoregulatory responses to environmental heating and cooling and other thermal challenges such as anesthesia and non-ionizing radiation. In this contribution, a dynamic simulation model is presented and used to predict human thermophysiological and perceptual responses for different applications and situations. The multi-segmental, multi-layered mathematical model predicts body temperatures, thermoregulatory responses, and components of the environmental heat exchange in cold, moderate, as well as hot stress conditions. The incorporated comfort model uses physiological states of the human body to predict thermal sensation responses to steady state and transient conditions. Different validation studies involving climate-chamber physiological and thermal comfort experiments, exposures to uncontrolled outdoor weather conditions, extreme climatic and radiation asymmetry scenarios revealed the model to predict physiological and perceptual responses typically within the standard deviation of the experimental observations. Applications of the model in biometeorology, clothing research, the car industry, clinical and safety applications are presented and discussed.