Renal cell carcinoma (RCC) describes a family of epithelial tumors arising from within the kidney. Each subtype of RCC presents a unique clinical picture with varied tumor biology, patient prognosis and response to treatment. Gene expression profiling offers the ability to analyze thousands of candidate genes in high-throughput arrays and has led to a greater knowledge of the molecular genetics of RCC. This powerful technology can identify RCC subtypes, recapitulating and refining the current histological classifications. Gene expression data also promise to advance current staging systems and improve prognostic information for patients and clinicians. Understanding the genetic signature of RCC tumors will allow for sophisticated application of systemic and targeted therapies, improving patient response and minimizing unnecessary exposure of patients to treatment toxicities. This article reviews the significance of gene expression analysis in the understanding of tumor biology and RCC treatment.