The 21st century has seen an explosion in the development of agents for renal-cell carcinoma (RCC), a malignancy previously considered refractory to systemic therapy beyond cytokine therapy. At this time, there are six US Food and Drug Administration (FDA)-approved agents available. In addition, there was a recent favorable review by the FDA's Oncologic Drugs Advisory Committee of a next-generation vascular endothelial growth factor receptor (VEGFR) inhibitor, axitinib (Inlyta); other agents are in advanced testing. Moreover, while VEGF- and mammalian target of rapamycin (mTOR)-targeted therapies have become the mainstay of RCC treatment, other new molecular targets and therapeutic approaches are being developed. The availability of active agents also brings opportunities for additional clinical maneuvers, such as neoadjuvant and adjuvant therapy, as well as a need for decisions on combinatorial therapeutics in the advanced disease setting. Together, these developments and the issues they raise pose important challenges for oncologists and cancer biologists, given the limited number of patients and resources available for studies and the urgent clinical needs of the patients and families affected by RCC.