Piriformis syndrome is a neuromuscular condition characterized by hip and buttock pain. This syndrome is often overlooked in clinical settings because its presentation may be similar to that of lumbar radiculopathy, primary sacral dysfunction, or innominate dysfunction. The ability to recognize piriformis syndrome requires an understanding of the structure and function of the piriformis muscle and its relationship to the sciatic nerve. The authors review the anatomic and clinical features of this condition, summarizing the osteopathic medical approach to diagnosis and management. A holistic approach to diagnosis requires a thorough neurologic history and physical assessment of the patient based on the pathologic characteristics of piriformis syndrome. The authors note that several nonpharmacologic therapies, including osteopathic manipulative treatment, can be used alone or in conjunction with pharmacotherapeutic options in the management of piriformis syndrome.