Osteoarthritis (OA) is a severely painful and debilitating disease of the joint, which brings about degradation of the articular cartilage and currently has few therapeutic solutions. 2-dimensional (2D) high-throughput screening assays have been widely used to identify candidate drugs with therapeutic potential for the treatment of OA. A number of small molecules which improve the chondrogenic differentiation of progenitor cells for tissue engineering applications have also been discovered in this way. However, due to the failure of these models to accurately represent the native joint environment, the efficacy of these drugs has been limited in vivo. Screening systems utilizing 3-dimensional (3D) models, which more closely reflect the tissue and its complex cell and molecular interactions, have also been described. However, the vast majority of these systems fail to recapitulate the complex, zonal structure of articular cartilage and its unique cell population. This review summarizes current 2D high throughput screening (HTS) techniques and addresses the question of how to use existing 3D models of tissue engineered cartilage to create 3D drug screening platforms with improved outcomes.