During the past 30 years, the evolution of endothermy has been a topic of keen interest to palaeontologists and evolutionary physiologists. While palaeontologists have found abundant Permian and Triassic fossils, suggesting important clues regarding the timing of origin of endothermy, physiologists have proposed several plausible hypotheses of how the metabolic elevation leading to endothermy could have occurred. More recently, molecular biologists have developed powerful tools to infer past adaptive processes, and gene expression mechanisms that describe the organization of genomes into phenotypes. Here, we argue that the evolution of endothermy could now be elucidated based on a joint, and perhaps unprecedented, effort of researchers from the fields of genomics, physiology and evolution.