The “genomics age” began over 20 years ago now, however, the availability of genomic data remain unevenly distributed across the tree of life, even within relatively well-known groups like amniotic vertebrates. In fact, most genomics-scale work has only accelerated in the past 5 years leading to new understandings of previously less clear phenomena, such as sex chromosome evolution. Although sex determination is a basic biological attribute and ubiquitous in vertebrates, mechanisms of sex determination vary from environmentally to genetically influenced. For example, mammals and birds have maintained stable, conserved sex chromosome systems over long evolutionary time periods, while other vertebrates, in contrast, undergo frequent sex chromosome transitions. Within squamate reptiles (>11,000 species of lizards and snakes), both evolutionarily stable and exceptional labile modes of sex chromosome evolution are thought to coexist. One group inferred to have an evolutionarily stable mode of sex determination is the infraorder Anguimorpha (a clade of charismatic taxa including monitor lizards, Gila monsters, and crocodile lizards), while the gecko lizards (infraorder Gekkota), show an exceptional lability with regard to sex chromosome transitions. Here, I summarize our recent work exemplifying how genomics have enhanced our ability to ask, and answer, complex questions in genome evolution and how these genome-scale insights can play a feedback role in helping us better understand and conserve the complex biology of the organisms with whom we share the planet.