Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of renal cell carcinoma (RCC) have paved the way for developments that may enhance early diagnosis, better predict prognosis, and improve survival. Reliable predictive factors are essential for the stratification of patients into clinically meaningful categories that can be used to provide patients with counseling regarding prognosis, select treatment modalities, and determine eligibility for clinical trials. The TNM (tumor, nodes, metastasis) staging system is currently the most extensively used staging system for RCC, but it has undergone systematic revisions as a result of emerging data. Comprehensive integrated staging systems that combine important clinical and pathological variables have been created in an attempt to improve prognostication. Although staging has improved with the development of integrated systems, the incorporation of molecular tumor markers are expected to revolutionize the staging of RCC. This article reviews the important molecular markers in RCC to date and discusses their role in the diagnosis, prognostication, and therapy of patients with RCC.