Osteoarthritis (OA) is the most common rheumatic pathology. It is related to aging, and is characterized mainly by cartilage degradation. Despite its high prevalence, currently available therapy is limited and focused on treating pain, which is the principal symptom of OA. Therefore, new treatments for OA that slow the progression of the disease are urgently needed. Because the progression of OA involves different tissues and complex biological processes, ongoing research is attempting to increase our knowledge of OA pathogenesis. New approaches for the characterization of molecules that play a role in OA have recently emerged. These include genomic, proteomic and metabolomic technologies. These techniques, coupled with sophisticated statistical methods, permit the simultaneous analysis of multiple targets, and have become very powerful tools in OA research. It is believed that proteomics will soon provide a much-needed novel therapeutic approach to treating OA. At present, many quantitative proteomics studies on the matrix metalloproteinases have led to the characterization of a plethora of new matrix metalloproteinase substrates while pharmaco-proteomics approaches have provided valuable information for target validation. This review will focus on the utility of proteomics for gaining insight into OA pathogenesis, identifying new therapeutic targets, and developing novel treatments.