Renal cell carcinoma (RCC) is a significant cause of mortality among genitourinary malignancies. It will be essential to integrate surgery and systemic therapy to improve outcomes in RCC. Despite substantial efforts to date and a newly US Food and Drug Administration (FDA)-approved agent, the role of adjuvant therapy following nephrectomy for clinically localized disease is complex. Following more than 50 years of failed efforts to identify effective adjuvant agents, pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, was demonstrated to improve survival in the adjuvant setting. In selected cases of locally advanced disease, neoadjuvant therapy may make unresectable disease resectable, enable partial nephrectomy, or shrink venous tumor thrombus. These theoretical goals remain in need of further study. For patients with metastatic RCC, the correct paradigm remains to be elucidated. In particular, the role of cytoreductive nephrectomy in the modern era is an active area of debate and research.