Adipose tissue (AT) has diverse and important functions in body insulation, mechanical protection, energy metabolism and the endocrine system. Despite its relative abundance in the human body, the clinical significance of AT in musculoskeletal (MSK) medicine, particularly its role in painful MSK conditions, is under-recognized. Pain associated with AT can be divided into intrinsic (AT as a primary pain generator), extrinsic (AT as a secondary pain generator) or mixed origin. Understanding AT as an MSK pain generator, both by mechanism and its specific role in pain generation by body region, enhances the clinical decision-making process and guides therapeutic strategies in patients with AT-related MSK disorders. This article reviews the existing literature of AT in the context of pain generation in the lower back and lower extremity to increase clinician awareness and stimulate further investigation into AT in MSK medicine.