The two-node bioheat model is widely used in thermal comfort standards and design tools. In recent years, there have been many new experimental studies and thermoregulatory models developed under stressful heat or cold conditions, but those have not been tested under the two-node model structure. Furthermore, limited validation studies of the two-node model revealed significant discrepancies in the prediction of skin temperature. This study collects relevant thermoregulatory models (six for sweating, three for skin blood flow and shivering, and four for sweat evaporation efficiency) and devises a methodology to compare the accuracy of various model combinations against experimental data. An improved model is developed and validated under heat and cold exposure conditions. The RMSE method is used to compare the accuracy of various model combinations and to optimize the proposed thermoregulatory model constants. The results reveal that only several model combinations can be considered as accurate for the core and skin temperature predictions, amongst which are the proposed models at the first rank.