Clear-cell renal cell carcinoma is characterized by the inactivation of the von Hippel-Lindau tumor suppressor gene, which results in an overproduction of vascular endothelial growth factor that promotes tumor angiogenesis, growth, and metastasis after binding with its receptor. The mammalian target of rapamycin signal transduction pathway is involved in the translation of hypoxia inducible factor-1 and vascular endothelial growth factor. Sunitinib, sorafenib, bevacizumab, and temsirolimus have improved clinical outcomes by inhibiting these tumorigenic pathways. Other multitargeted tyrosine kinase inhibitors (lapatinib, axitinib, pazopanib) and antiangiogenic agents (lenalidomide) have also demonstrated activity in early studies. Combinations of these agents are being evaluated. Clinical trials designed to further assess these and other agents need to be vigorously supported.