These are indeed exciting times in the study of RCC. No longer should the clinician view RCC as a single entity, nor should the researcher pose basic questions without considering the biologic diversity of this tumor. The success of novel targeted therapeutic strategies will depend on the systematic study of genetic and epigenetic events and their relationship to aberrant protein expression and function, and an understanding of the permissive microenvironment that allows the tumor to be sustained. These studies must be correlated in a rigorous fashion to clinical parameters and outcomes. Progress against this elusive tumor will require a continuous translational dialogue between laboratory and clinical investigators.