Recent developments have involved a series of novel agents that produce clinical benefit in patients with advanced clear-cell renal cell carcinoma (RCC). The molecular characteristics of RCC, pathways involved in growth and progression, and development of targeted therapeutic approaches have become the focus of many investigators in the past decade. A variety of genetic abnormalities, molecular markers and drugs that target these markers or alter the genetic expression of certain regulatory proteins, have been identified and might have clinical significance for prognosis and treatment. However, specific markers associated with RCC and further development of novel single or combination targeted therapies is now required. An understanding of the complicated and unique biologic behavior of RCC and its various histologic subtypes is crucial for the continued development of novel and targeted therapies.