The treatment of advanced renal cell carcinoma (RCC) has evolved dramatically over the past 30 years, as has a better understanding of the biology of the disease, knowledge of multiple subtypes with distinct molecular abnormalities, and improved comprehension of the perturbed pathways that lead to the development and growth of RCC. This is no longer a monolithic disease, although the majority of tumors are of the clear cell subtype. However, progress is being made in other subtypes as well, as molecular profiles are better understood and as new agents show activity. Immunotherapies remain a major category of treatment, from cytokines to checkpoint inhibitors to ex vivo activated cellular therapy. Antiangiogenesis tyrosine kinase inhibitors are also an important part of the armamentarium. Because these approaches have evolved, we are now in the era of combination therapy using agents of differing mechanisms to try to achieve synergy to increase response rates and create durable responses leading to prolonged survival. Renal cell carcinoma as a tumor is unique in that there has always been a subset of patients who achieve complete responses that last for many years without subsequent treatment. Thus, the goal of further development is to enlarge this subset using new therapeutic approaches and to achieve further durable responses and treatment-free survival.