The important requirement that COST Action 730 demanded of the physiological model to be used for the Universal Thermal Climate Index (UTCI) was its capability of accurate simulation of human thermophysiological responses across a wide range of relevant environmental conditions, such as conditions corresponding to the selection of all habitable climates and their seasonal changes, and transient conditions representing the temporal variation of outdoor conditions. In the first part of this study, available heat budget/two-node models and multi-node thermophysiological models were evaluated by direct comparison over a wide spectrum of climatic conditions. The UTCI-Fiala model predicted most reliably the average human thermal response, as shown by least deviations from physiologically plausible responses when compared to other models. In the second part of the study, this model was subjected to extensive validation using the results of human subject experiments for a range of relevant (steady-state and transient) environmental conditions. The UTCI-Fiala multi-node model proved its ability to predict adequately the human physiological response for a variety of moderate and extreme conditions represented in the COST 730 database. The mean skin and core temperatures were predicted with average root-mean-square deviations of 1.35 ± 1.00°C and 0.32 ± 0.20°C, respectively.