The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in at least 50% of sporadic clear-cell renal cell carcinoma (RCC). This leads to a pseudohypoxic state in which the pVHL complex does not degrade hypoxia-inducible factor. Subsequent intracellular hypoxia-inducible factor accumulation results in increased production of growth factors such as VEGF, responsible for angiogenesis, tumor proliferation and mitogenesis. Recently, a number of strategies have been designed to specifically target these pathways. The VEGF, its related receptor and the mammalian target of rapamycin (mTOR) signal transduction pathway, in particular, have been utilized as therapeutic targets. Clinical trials have demonstrated the survival benefit of these agents, particularly in clear-cell RCC. Today, sunitinib is recommended as first-line therapy for intermediate- or low-risk patients with metastatic RCC. Sorafenib is advised as second-line therapy, whereas temsirolimus is generally recommended as first-line treatment in high-risk patients. Everolimus is the new standard following sunitinib. High-risk patients appeared to benefit less than low-risk patients from bevacizumab plus IFN-alpha therapy. High-dose IL-2 has been proven effective in prolonging progression-free survival or overall survival, depending on risk group selection criteria. Although novel agents show a consistent effect as measured by objective response, no currently available data demonstrate that these agents will cure any patient.