This review describes the potential of disease-modifying osteoarthritis drugs (DMOADs), distinguishing between preventing, retarding, stopping, and reversing disease and what might be clinically meaningful. The authors also describe whether there is any evidence to suggest that one can modify disease, and whether the current tissue that is predominantly focused on, namely, cartilage, is an appropriate target. The methodologic approaches and other obstacles to demonstrating efficacy of these agents in clinical trials are considered. This discussion is a narrative review in a field that is rapidly evolving. It is hoped the reader appreciates the complexity of the field and the likely road ahead to DMOAD development.