The management of advanced renal cell carcinoma (RCC) is undergoing a revolution, with the introduction of new agents and surgical paradigms. Thoughtful integration of diagnostic, surgical and medical approaches to the patient is paramount for disease control. Methods of risk stratifying kidney cancers are reviewed, as well as mechanisms of action of newer drugs approved in advanced metastatic kidney cancer. These drugs present opportunities for application to patients in an earlier stage of disease, and adjuvant RCC trials designs are discussed. Improvements have been made in the understanding of the molecular and genetic basis of RCC, both for causative and prognostic markers, with models addressing prediction of tumor behavior and therapeutic targets. Practice patterns have shifted from cytokine therapies to targeted molecular approaches, particularly emphasizing the VEGF pathway, related intracellular kinases and the mammalian target of rapamycin. Autologous vaccine adjuvant studies are maturing. In conclusion, elucidation of specific genes, proteins and aberrant molecular pathways associated with kidney cancer are ongoing. These new agents may lead to opportunities to improvement of disease-free survival through therapy in the adjuvant setting.