Historically, systemic therapies for metastatic renal cell carcinoma (RCC) have met with minimal success. Recently, an improved understanding of cancer biology has been translated into therapies that target pathways critical for RCC growth and survival and produce more robust clinical impact. The risks and benefits of several approaches to systemic therapy in metastatic RCC are reviewed. The need for chronic therapy of novel agents and potential for toxicity raise questions in regard to the timing of therapy and value of combination therapy over sequential single agents. Further insight into the biology of response, resistance, and toxicity is needed to allow for rational patient selection and enhanced application of systemic therapies. As new standard therapies for metastatic RCC emerge, clinical trial conduct remains a priority to further optimize patient outcome.