Understanding biology at the systems level is a powerful method for discovery of previously unrecognized molecular pathways and mechanisms in human disease. The application of proteomics to arthritis research has lagged behind many other clinical targets, partly due to the unique biochemical properties of cartilage and associated biological fluids such as synovial fluid. In recent years, however, proteomic-based studies in cartilage and arthritis research have risen sharply and have started to make a significant impact on our understanding of joint disease, including the discovery of new and promising biomarkers of cartilage degeneration, a hallmark of arthritis. In this review we will make the case for the ongoing proteomic analysis of cartilage and other tissues affected by joint disease, overview some of the core proteomic techniques and discuss how the challenge of cartilage proteomics has been met through technical innovation. The major outcomes and information obtained from recent proteomic analysis of synovial fluid, cartilage and chondrocytes will also be described. In addition, we present some novel insights into post-translational regulation of cartilage proteins, through proteomic identification of proteolytic fragments in mouse cartilage extracts and explant culture media. We conclude with our prediction of how emerging proteomic technologies that have yet to be applied in arthritis research are likely to contribute further important information.