Obesity is widely acknowledged as a risk factor for both the incidence and progression of osteoarthritis. Loss of at least 10% of body weight is recognized as a cornerstone in the management of obese patients with osteoarthritis, and can lead to significant improvement in symptoms, pain relief, physical function, and health-related quality of life. However, questions still remain surrounding optimal management and whether structural disease progression can be arrested. Given the significant health, social, and economic burden of osteoarthritis, especially in obese patients, it is imperative to advance our knowledge of osteoarthritis and obesity, and apply this to improve care and outcomes. This chapter overviews what is known about osteoarthritis, obesity, and weight loss and discusses current key challenges in management and maintenance of weight loss for overweight and obese individuals with osteoarthritis.