High-risk localized renal cell carcinoma represents a therapeutic challenge with high recurrence rates and poor survival with nephrectomy alone. Multiple agents targeting angiogenic and immunologic pathways have demonstrated remarkable efficacy in the metastatic setting but have failed to replicate similar successes in localized disease. Study results with adjuvant anti-angiogenic therapies may have been compromised by the high incidence of treatment discontinuations or dosage reductions secondary to intolerable side effects. Improving patient selection could play a major role in improving outcomes. Multiple models exist to predict survival but require improved accuracy in identifying recurrence to justify exposing patients to therapies that could significantly impair quality of life. Further understanding of pathological and molecular mechanisms of recurrence is required. Novel tools like gene recurrence scores are emerging to improve prognostication for patient selection. Immunotherapeutic approaches using check point inhibition have the potential to achieve sustained remissions with a significantly improved toxicity profile. Amplifying the immune response with a combination of neoadjuvant and adjuvant therapy to exploit the larger antigenic burden prior to nephrectomy has the biologic potential for making significant improvements in efficacy.