Renal cell carcinoma (RCC) is not a single entity, rather it is a term defining a group of histologically distinct tumors arising in the renal parenchyma. Each histologic subtype is clinically and genetically unique. It is our understanding of the genetic basis for these cancers that has led to the variety of targeted systemic therapies now available in RCC. This review will cover the basic tumor biology behind each histology, as well as the associated therapeutic targets identified thus far. Mechanisms and associated side effects of the currently available drugs will be examined. Completed clinical trials will be discussed, leading into the rationale behind currently active trials, and future directions for drug development.