There has been a recent expansion of therapeutic options in metastatic renal cell carcinoma (RCC) targeted at the vascular endothelial growth factor and mammalian target of rapamycin pathways, which are fundamental to the biology of RCC. These treatment options have similarities in antitumor effect but also important differences in regards to clinical effects, toxicity and patient populations in which they have been investigated. Further, issues regarding the role of debulking nephrectomy, timing of therapy, and appropriate sequencing of agents have emerged as clinically relevant. There are thus potentially many different treatment approaches to each metastatic RCC patient. This review discusses how to integrate the available data regarding targeted therapy in metastatic RCC into personalized cancer care.