Cytogenetic and molecular genetic analyses of uterine leiomyomata (UL) have revealed recurrent somatic mutations. Additionally, the high frequency of UL, findings from genetic epidemiologic research and differences in disease prevalence and severity across racial groups suggest common germline variants influence predisposition. In this chapter, somatic and germline mutations in UL biology and pathogenesis are considered, evolving knowledge of constitutional mutations predisposing to pediatric cancers is explored in the context of UL and recent findings established through advanced genomic technologies are synthesized into a model of how somatic and germline variants might interplay in tumorigenesis.