Germline mutations in BRCA1 and BRCA2 predispose to common human malignancies, most notably tumors of the breast and ovaries. The proteins encoded by these genes have been implicated in a plethora of biochemical interactions and biological functions, confounding attempts to coherently explain how their inactivation promotes carcinogenesis. Here, I argue that tumor suppression by BRCA1 and BRCA2 originates from their fundamental role in controlling the assembly and activity of macromolecular complexes that monitor chromosome duplication, maintenance, and segregation across the cell cycle. A tumor-suppressive role for the BRCA proteins as “chromosome custodians” helps to explain the clinical features of cancer susceptibility after their inactivation, provides foundations for the rational therapy of BRCA-deficient cancers, and offers general insights into the mechanisms opposing early steps in human carcinogenesis.