We are only just beginning to appreciate the tremendous amount of genomic diversity that exists within and between individuals. Surprisingly, most of this diversity derives from structural variations (SVs) — the large, regionally acting mutations once thought to be exceptionally rare and deleterious genomic lesions. A single SV — be it a chromosomal gain or loss, copy number variation, or translocation — can affect thousands to millions of base pairs of the genome. Thus, even as individual variations, SVs are potent sources of mutation likely to impart significant functional consequences to the individuals that harbor them. This potent mutagenic capacity makes SVs important drivers of adaptation, and evolution; but it also renders them common sources of congenital and somatic disease. Though we have continued to learn more about the mutational events that produce new SVs, the discovery of their ubiquity has challenged fundamental tenets of genomics. At the molecular level, the prevalence of SVs prompts critical open questions about how chromosome integrity is maintained over time; more broadly, the pervasiveness of such large-scale variations complicates established models of genotype-phenotype relationships and evolutionary dynamics. Our team is exploring many fascinating and important biological questions focused on understanding how SVs arise in the genome, and how these variations contribute to genome stability and evolution, phenotypic diversity, and cellular and organismal fitness.