Diet selection in mammalian herbivores is thought to be primarily governed by intrinsic properties of food, such as nutrient and plant secondary compound (PSC) contents, and less so by environmental factors. However, several independent lines of evidence suggest that the toxicity of PSCs is mediated, in part, by ambient temperature and that the effect of small changes in ambient temperature is on par with several fold changes in PSC concentration. This review describes the disparate lines of evidence for temperature-dependent toxicity and the putative mechanisms causing this phenomenon. A model is described that integrates thermal physiology with temperature-dependent toxicity to predict maximal dietary intake of plant secondary compounds by mammalian herbivores. The role of temperature-dependent toxicity is considered with respect to the observed changes in herbivorous species attributed to climate change. Possible future investigations and the effects of temperature-dependent toxicity on other endotherms are presented. Temperature-dependent toxicity has the potential to apply to all endotherms that consume toxins. The effects of temperature-dependent toxicity will likely be exacerbated with increasing ambient temperatures caused by climate change.