<p>Osteoarthritis (OA) is a painful disorder of the synovial joints characterized by dysfunctional cellular metabolism and extracellular matrix degradation that activates maladaptive repair responses, including pro-inflammatory pathways of innate immunity. OA has historically been viewed as an unavoidable consequence of ageing owing to wear-and-tear of the joint. Most strategies to mitigate OA have primarily focused on the articular cartilage and, more recently, other specific joint tissues, which limits understanding of OA as a systemic disease beyond the joint. Preclinical and clinical data support a paradigm shift in understanding OA as a disease of the whole person, focusing on changes throughout the body that both promote and are caused by OA. This shift provides novel insights into why preclinical research findings have not been successfully translated into clinical therapies. Moreover, a viable strategy for OA drug development could be to treat pain separately from OA structural damage. Challenging classically held views that lack evidence or have been disproven is required for progress. We explore some key emerging questions that should be carefully considered in future OA studies. Adapting and integrating new technologies, techniques, and tools into the rapidly evolving understanding of OA could lead to the development of drugs that might not only treat OA but also provide mechanistic insight into other conditions that result from the dysregulation of systemic factors or from the communication breakdown in inter-organ crosstalk. Such developments would reposition OA researchers from adapting approaches from other fields of science and medicine to leaders in the fight against chronic disease.</p>