Synopsis Osteoarthritis (OA) of the hip and knee is among the leading causes of global disability, highlighting the need for early, targeted, and effective treatment. The benefits of exercise therapy in people with hip and knee OA are substantial and supported by high-quality evidence, underlining that it should be part of first-line treatment in clinical practice. Furthermore, unlike other treatments for OA, such as analgesia and surgery, exercise therapy is not associated with risk of serious harm. Helping people with OA become more physically active, along with structured exercise therapy targeting symptoms and impairments, is crucial, considering that the majority of people with hip and knee OA do not meet physical activity recommendations. Osteoarthritis is associated with a range of chronic comorbidities, including type 2 diabetes, cardiovascular disease, and dementia, all of which are associated with chronic low-grade inflammation. Physical activity and exercise therapy not only improve symptoms and impairments of OA, but are also effective in preventing at least 35 chronic conditions and treating at least 26 chronic conditions, with one of the potential working mechanisms being exercise-induced anti-inflammatory effects. Patient education may be crucial to ensure long-term adherence and sustained positive effects on symptoms, impairments, physical activity levels, and comorbidities. J Orthop Sports Phys Ther 2018;48(6):439-447. Epub 18 Apr 2018. doi:10.2519/jospt.2018.7877.