The incidence rates of renal cell carcinoma (RCC) have continued to rise with 58,000 new cases in the United States. RCC has notoriously been refractory to traditional chemotherapeutic including radiation and cytokine therapies. The advent of the use of molecularly targeted therapies for RCC has significantly improved the standard of care. Yet, there still remains room for improvement as many of the current therapies are limited by acquired resistance and dosing restrictions due to toxicity. In this review we discuss many potential therapeutic targets that have been suggested for development as advancements are made in discovering the underlying molecular biology of RCC. Among the targets that discussed are additional targets within the well-established VHL/HIF axis, the PI3K/AKT/mTOR pathway, independent targets, and those identified by synthetic lethality screens.