In 2006, approximately 38,890 patients in the United States will be diagnosed with kidney tumors. Roughly 90% of those will be renal cell carcinomas (RCCs). Of those patients, 30% will have metastatic disease at the time of diagnosis. An additional 20% to 30% with clinically localized disease at the time of nephrectomy will subsequently develop metastatic disease for which there are few reliable, effective treatments. In 2006, no clinically proven, adjuvant therapy exists for patients at high risk of relapse following definitive surgical therapy. In the past, several strategies have been tried unsuccessfully in the adjuvant setting, including, radiotherapy, chemotherapy, immunotherapy, and hormonal therapy. An improved understanding of the molecular basis of RCC has allowed for a more targeted approach to therapy. Several newer agents, including thalidomide, vitespin (heat shock protein [hsp] 96 vaccine), WX-G250, sorafenib, and sunitinib, are either currently under investigation in the adjuvant setting or being considered for future adjuvant trials. Here, we discuss the past, present, and future of adjuvant therapy for RCC patients at high risk for relapse following definitive surgical therapy.