Less than 20 years ago, the von Hippel-Lindau (VHL) gene was discovered and associated with sporadic renal cell carcinoma (RCC). Since then, researchers and clinicians have labored to better understand the biology driving RCC tumor progression and provide means to predict patient survival and response to therapy. Studies surrounding VHL inactivation and downstream effects continue to provide insights into these areas. Besides studies of this primary pathway, cytogenetic studies, gene expression analyses, tissue microarrays, serum proteomics, genomic resequencing, and microRNA profiling have yielded greater understanding of RCC biology and clinical presentation, and have led to a rich understanding of the heterogeneity of this disease. We review the current state of research investigations into the molecular biology of RCC, and discuss the applications to currently used clinical prognostic nomograms.