The rationale behind developing sustained release microsphere formulations of non-steroidal anti-inflammatory drugs (NSAIDs) administered via the intra-articular (IA) route is to minimise the systemic bioavailability and attendant side-effects associated with oral drug administration. Overall dose is reduced whilst therapeutic benefit within the joint is maintained. The potential benefits of IA therapy for osteoarthritis (OA) are not achieved using currently available medications and delivery vehicles due to the rapid clearance of therapeutic substances from the synovial space. There is a need for sustained release delivery systems if the potential of IA drug administration is to be realised. Rationally designed microspheres taken up by synovial macrophages offer a strategy to sustain drug delivery within the joint, and to deliver NSAIDs directly to pivotal inflammatory cells. The efficacy of microsphere candidates may be evaluated in large animal models of OA. The principles of IA microsphere drug delivery may also be applicable to other classes of drugs.