Squamates exhibit some of the most extreme and fascinating biological adaptations among vertebrates, including the production of a wide diversity of venom toxins. The rapid accumulation of genomic information from squamate reptiles is generating important new context and insights into the biology, the regulation and diversity of venom toxins, and the evolutionary processes that have generated this diversity. It is an exciting time as we discover what the unique aspects of the squamate genome can tell us about the molecular basis of such interesting and diverse phenotypes and explain how the extreme adaptations of squamate biology arose. This chapter reviews what is known about major patterns and evolutionary trends in squamate genomes and discusses how some of these features may relate to the evolution and development of unique features of squamate biology and physiology on the whole, including the evolution and regulation of venom toxins. It also discusses current challenges and obstacles in understanding squamate genome size, diversity, and evolution, and specific issues related to assembling and studying regions of squamate genomes that contain the genes and regulatory regions for venom toxins. Evidence is presented for a relatively constant genome size across squamates even though there have been major shifts in genomic structure and evolutionary processes. Some genomic structural features seem relatively unique to squamates and may have played roles in the evolution of venom toxins.