Renal cell carcinoma (RCC) is associated with a poor prognosis and there is a need for biomarkers to assist at all stages of disease management including diagnosis, prognosis, monitoring for relapse and predicting response to therapy. Additionally, identification of new therapeutic targets is a priority. Increased understanding of disease pathogenesis and the molecular changes underlying tumour formation is essential to assist in the rational design of such molecules. As the technologies underlying proteomics-based research have developed, they have been applied extensively to the analysis of cancers including RCC, with tissues, cell lines and biological fluids being used for analysis. A number of approaches have been adopted including two-dimensional polyacrylamide gel electrophoresis and mass spectrometry profiling of intact proteins, shotgun mass spectrometry-based profiling at the peptide level, antibody arrays and strategies analysing the immune response to tumours with a view to identifying tumour-associated antigens. Although these studies are still at a relatively early stage, promising results have been reported with some being taken forward to preliminary validation. The challenge now is to build on these initial efforts, focusing particularly on interrogating the less readily accessible, lower abundance proteome and implementing large-scale validation studies to develop potential markers, antigens and targets and facilitate translation of suitable findings into the clinic.