The arrival of next-generation nucleotide sequencing techniques more than a decade ago promised transformative change in comparative physiology by providing unprecedented insights into animal function. Sequenced, and well-annotated genomes have enabled physiologists to identify candidate genes and proteins involved in physiological adaptations through genome-wide associated studies, targeted and non-targeted transcriptomics, proteomics, and other ‘omics’ approaches. I will share how our work utilizing the genome of the extremely anoxia-tolerant Western painted turtle has elucidated the mechanisms underlying the adaptations of heart and brain to cold temperatures and anoxia and the interactive effects of development. I will also share some of the shortcomings of these approaches that we have discovered, and how their insight into the physiological function of turtles has been limited.