Disclosed herein is a method of identifying a tumor biomarker. In one example, a tumor biomarker is identified by obtaining a peripheral biological fluid sample from a subject with a tumor as well as a tumor sample and an adjacent non-tumor sample from such subject. A protein expression profile is detected in the peripheral biological fluid sample, tumor sample and adjacent non-tumor sample. The protein expression profiles of the peripheral biological fluid sample, tumor sample and adjacent non-tumor sample are then compared, wherein an increase in expression of a specific protein in the tumor sample and peripheral biological fluid sample but not in the adjacent non-tumor sample indicates that the specific protein is a biomarker of the tumor. Also disclosed herein is a gene profiling signature that can be used to diagnosis a subject with renal cell carcinoma (RCC) or to identify agents with therapeutic potential to treat RCC. Thus, methods of diagnosing a subject with RCC are disclosed. Methods are also provided for identifying agents that alter an activity of a RCC biomarker.