The introduction of targeted therapy in metastatic renal cancer patients provides a whole array of individual therapeutic options. The basis for this treatment is the inactivation of the von Hippel-Lindau tumor suppressor gene, resulting in high expression of pro-angiogenic growth factors, e.g. vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). This provides the rationale for targeting these pathways in clear cell renal cell carcinomas by small molecule inhibitors. This article gives a review on clinical trials with sunitinib, sorafenib, and temsirolimus in patients with advanced renal cell carcinoma and shows how promising treatments can emerge from an understanding of the molecular genetics and signaling pathways of tumors. However, a predictive marker, e.g. specific mutations associated with drug-resistant or responsive tumors, has not yet been identified and is paramount for the future.