Renal cell cancer (RCC) is the most lethal of the urological cancers and accounts for 3% of all adult malignancies. Despite numerous recent advances in diagnostic imaging, surgical therapy, and basic molecular understanding, many patients still experience metastatic disease. For metastatic disease patients, response rates to conventional therapies rarely exceed 15% to 25% and are associated with serious adverse effects. The recent development of novel targeted therapies based on the precise biological pathways deregulated in a particular patient has paved the way for individualized, targeted patient management. Nevertheless, to achieve this goal, it is important to delineate the molecular mechanisms underlying cancer development and progression. Genomic approaches have revolutionized the field of cancer research and have led to the rapid discovery of multiple, parallel disease hypotheses, which ultimately have to be validated in large cohorts of patients and in downstream biological experiments for translation into clinical applications. The variable course of RCC and, until recently, a paucity of therapeutic options in the event of metastasis have led to the search for diagnostic and prognostic markers. We and others have used transcriptional profiling to classify different subtypes of RCC and to identify subtype- and metastasis-specific gene signatures predictive for outcome. We discuss herein recent genomic approaches to RCC and the emerging biological pathways underlying RCC development and progression. We also speculate how genomics may affect drug development and the management of patients with RCC.