Thermal limits mark the boundaries of ectotherm performance, and are increasingly appreciated as strong correlates and possible determinants of animal distribution patterns. The mechanisms setting the thermal limits of ectothermic animals are under active study and rigorous debate as we try to reconcile new observations in the lab and field with the knowledge gained from a long history of research on thermal adaptation. Here, I provide a perspective on our divided understanding of the mechanisms setting thermal limits of ectothermic animals. I focus primarily on the fundamental differences between high and low temperatures, and how animal form and environment can place different constraints on different taxa. Together, complexity and variation in animal form drive complexity in the interactions within and among levels of biological organization, creating a formidable barrier to determining mechanistic cause and effect at thermal limits. Progress in our understanding of thermal limits will require extensive collaboration and systematic approaches that embrace this complexity and allow us to separate the causes of failure from the physiological consequences that can quickly follow. I argue that by building integrative models that explain causal links among multiple organ systems, we can more quickly arrive at a holistic understanding of the varied challenges facing animals at extreme temperatures.