Single-gene disorders that predispose to cancer afford a unique window into the mechanisms of carcinogenesis. I argue that the instability in chromosome structure and number provoked by inactivation of the breast cancer–susceptibility genes BRCA1 and BRCA2 arises from the distinct functions served by their products in DNA repair or mitosis, explains many features of cancer pathogenesis in this setting, and has important implications for treatment. The chromosomal instability model proposed here suggests a conceptual framework for the connections between chromosomal aberrations and cancer.