The complex structure of articular cartilage, the connective tissue lining diarthrodial joints, enables this tissue to dissipate compressive loads but also appears to hinder its repair ability. At best, both natural and surgical repair attempts replace the highly ordered extracellular matrix of native articular cartilage with fibrous repair tissue of inferior mechanical properties. Numerous bioactive molecules closely regulate the cellular processes in healthy and degenerative articular cartilage. Accordingly, this review outlines the roles of important signaling molecules in cartilage tissue. In addition, drug delivery strategies, aimed at utilizing these bioactive agents to prevent inflammation, to regulate extracellular matrix metabolism, and to control cellular activities, are discussed. As scientists gain further insight into the complex signaling cascades of articular cartilage, continued refinement of drug delivery systems is necessary to develop effective clinical therapies for articular cartilage repair.