The search for efficient strategies for preventing cartilage degradation in osteoarthritis is a key issue in rheumatology. Proteomic technologies may help to identify new targets for pharmacological intervention as well as to contribute toward the identification of diagnostic biological markers. Proteomic analysis of osteoarthritis can be performed at different levels, including the cartilage itself, biological fluids such as synovial fluid or serum, or cell culture systems that can be used to investigate the functions of chondrocytes. Early proteomic studies of osteoarthritis have typically involved two-dimensional electrophoresis or liquid chromatography coupled to mass spectrometry, as well as protein microarrays. In the future, differential proteomic analyses that involve recently developed and powerful technologies such as those utilizing isotope-coded affinity tags, stable isotope labeling by amino acids in cell culture, or surface-enhanced desorption/ ionization time-of-flight analysis, should substantially improve our knowledge of the pathophysiology of osteoarthritis through the identification of novel disease markers.