Renal cell carcinoma (RCC) is characterized by being the most resistant malignancy to cytotoxic chemotherapy. Few patients with mRCC benefit from cytokine-based immunotherapy with interleukin-2 and/or interferon-alpha. Recent advances in the understanding of molecular mechanisms and genetics of RCC have led to the identification of new targets such as vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR). Activation of these pathways in RCC is associated with tumor angiogenesis, proliferation and metastasis. Recently, six antian-giogenic agents, sorafenib, sunitinib, pazopanib, bevacizumab (in comibination with interferon), temsirolimus and everolimus, have shown clinical activity in metastatic RCC. In this review, we focus on the molecular pathogenesis of RCC and novel therapeutic agents.