The management of patients with metastatic renal cell carcinoma (RCC) has changed dramatically over the past few years. Nephrectomy remains an important intervention for localized RCC but systemic therapy is the mainstay of treatment for patients who relapse after surgery or who have metastatic RCC. Before 2005, medical therapies for RCC were limited to cytokine therapies, which are very toxic and benefit only a small percentage of patients. In 2017, therapeutic agents now include kinase and immune checkpoint inhibitors. Contemporary research with these agents is now focusing on combinatorial and perioperative therapy. The field is now faced with the evolving challenge of how to select the best therapy for each patient during their natural history of disease, which has created a strong interest in modern sequencing and molecular approaches to identify biomarkers to personalize treatments. New therapeutic agents and approaches are associated with different toxicities and financial burdens, which require consideration of value by measuring clinical benefit, toxicity, and the cost of each drug with an organized framework. In this Review, we discuss the mechanisms underlying RCC and how improved molecular understanding helped the development of therapies, as well as biomarkers of response to treatment. We also discuss the value of these agents and their impact on personalization of therapy and drug development for RCC.