Squamates (lizards, snakes, and their kin such as amphisbaenians, or “worm lizards”) represent the world's most diverse clade of terrestrial vertebrates with ∼11,000 described extant species, representing key components in many of the world's most diverse ecosystems. With an evolutionary history dating back at least to the Middle Triassic at 242 Ma, the squamate Tree of Life also features numerous diverse but extinct branches, with hundreds of fossil species found all over the world. Despite their biological relevance both today and in the geological past, there remains a centuries-old controversy on how the major lineages of squamates are related to each other, with a direct impact on studies in ecology, evolution, paleontology, toxinology, and other fields. Here, we provide a historical overview of this long research tradition, from 19th century naturalists to 21st century phylogenomics, with special emphasis on several recent advances over the last two decades. These insights have had a dramatic effect on our understanding of the squamate Tree of Life and clarify several possible future research agendas. We provide an integrative perspective derived from genomics, morphology, and the fossil record and propose several points of synthesis in our current knowledge of broadscale squamate evolution and systematics. Key topics of interest include dating the origin and early evolution of lizards, the phylogenetic origin of snakes, the evolution of venom, recent agreements between morphological and molecular squamate evolutionary trees, genomic patterns of evolution, and the integration of morphological and molecular data sets. We conclude by providing perspectives on possible advancements in the field, directing researchers to promising future lines of investigation that are necessary to further expand our synthetic knowledge of squamate evolution.