In general, debulking neprhectomy is still considered for metastatic RCC patients with primary tumor in place, assuming good performance status. Initial systemic therapy should consider high-dose IL-2 for the highly select patient. One reason for initial consideration of this therapy is the less certain risk/benefit profile if employed after targeted therapy. Notably, due to its potential toxicity and emergence of new effective and more tolerable drugs, IL-2 has become a less favorable and subsequently a less utilized therapeutic tool in the current era. Otherwise, VEGF-targeted therapy is the treatment of choice, preferably on a clinical trial. Off trial, sunitinib has long been favored but pazopanib is gaining more use for tolerance pending the comparative trial. Continued VEGF targeting is favored by these authors given the underlying biology of RCC and the prospective clinical data, noting no direct comparison of mTOR and VEGF agents has yet occurred. Maintaining patient dose is critical and requires optimal supportive care and appreciation/early intervention for toxicity. Predictive biomarkers are desperately needed, and enrollment on clinical trials remains a priority to optimize patient outcome.