Several targets have been identified for the therapy of metastatic renal cell carcinoma (RCC). The recognition of hypoxia-inducible factor-α signaling in the pathogenesis of clear-cell RCC has led to widespread study of angiogenesis inhibitors. Understanding this molecular pathogenesis of RCC led to a rapid evolvement of new systemic therapies, with seven targeted therapies approved and several more agents in late-stage clinical development. Due to the results of the currently used targeted therapies, the progression-free survival could be prolonged and the overall survival in sequential therapy can reach up to 40 months. The development of validated guidelines for sequential treatment or combination of targeted therapy remains a current challenge.