Renal cell cancer (RCC) is a heterogeneous disease consisting of different histologic types. Major advances have been accomplished during the last 15 years in our understanding of the genetic events that initiate RCC. These advances were greatly facilitated by meticulous clinical description and registration of patients with familial predisposition to RCC. The cloning of the susceptibility genes that underline familial predisposition to RCC has offered entry points into the signaling pathways that are also deregulated in sporadic RCC. Biochemical studies of these signaling pathways and target validation experiments have already culminated in the discovery and clinical application of small molecules with promising activity in RCC. In this article, we highlight the molecular genetic features of RCC that are more directly related to identification and validation of promising targets for molecular therapy.