Originally identified as a lubricating component of synovial fluid, the mucinous glycoprotein lubricin is now recognized to be a major chondroprotective macromolecule which localizes to, and affords boundary lubrication of, articular cartilage surfaces. Lubricin is synthesized in the joint by cells of the synovial lining, as well as by tendon and meniscal cells, in addition to its expression by superficial zone chondrocytes (wherefrom it was initially described as ‘superficial zone protein’, or SZP). Genetic ablation of lubricin synthesis in mice, or in humans with a rare autosomal recessive disorder, CACP syndrome, results in accelerated cartilage damage and joint failure, with associated non-inflammatory synovial hypercellularity/thickening and subintimal capsular fibrosis. In addition, data from joint injury models have demonstrated alterations in lubricin expression, as well as elevated cartilage friction levels which may be attenuated by lubricin restitution. Based in part on the aforementioned findings, several independent laboratories have explored the potential utility of lubricin supplementation for the treatment of OA. Such investigations have included augmentation via intraarticular injections of natural or recombinant lubricin molecules, and these campaigns have been successful in preclinical (rodent) models of OA, resulting in reduced cartilage damage and OA scores. Additional beneficial consequences of lubricin administration have also been demonstrated, including protection against chondrocyte apoptosis, and evidence for symptom (pain) modification as measured by normalization of differential weight-bearing, or gait asymmetry, between diseased and contralateral limbs. An important consideration for such therapeutic strategies relates to the ‘residence time’ of exogenously applied lubricin within the joint. Whereas soluble molecules present in synovial fluid exhibit a relatively rapid rate of clearance, lubricin bound to tissue (i.e. cartilage) surfaces can exhibit a greater longevity, and maximizing lubricin retention and exposure within the joint would seem to bear high importance for successful translational applicability. In this regard, other opportunities for providing enduring lubricin levels may include gene therapy-based approaches wherein lubricin is delivered via, for example, viral-based vectors, and for which preclinical proof-of-principle studies have also recently been reported. The ultimate clinical development of lubricin supplementation therapies will be dependent on a number of critical factors. Of high importance is the technical capability and capacity to produce validated and cost-effective materials (i.e. recombinant lubricin molecules). Equally necessary are contingencies for identifying a responsive patient population, and establishing appropriate, clinically meaningful and regulatory agency-approved endpoints which can be robustly measured. As with any therapeutic candidate development paradigm, toxicologic and safety pharmacology evaluations should indicate a low level of risk associated with dosing and administration procedures, thereby enhancing the rationale for investing in such a modality for the treatment of OA.