Osteoarthritis (OA) is a prevalent and disabling condition for which few safe and effective therapeutic options are available. Current approaches are largely palliative and in an effort to mitigate the rising tide of increasing OA prevalence and disease impact, modifying the structural progression of OA has become a focus of drug development. This Review describes disease modification and discusses some of the challenges involved in the discovery and development of disease-modifying OA drugs (DMOADs). A variety of targeted agents are in mature phases of development; specific agents that are beyond preclinical development in phase II and III trials and show promise as potential DMOADs are discussed. A research agenda with respect to disease modification in OA is also provided, and some of the future challenges we face in this field are discussed.