In 1987, synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome was proposed as an umbrella term for a group of diseases with similar musculoskeletal manifestations, in particular hyperostosis of anterior chest wall, synovitis, and multifocal aseptic osteomyelitis, observed in association with dermatologic conditions such as palmoplantar pustulosis, severe acne, and hidradenitis suppurativa. Despite recent advances in our understanding of the epidemiologic, pathophysiologic, and immunogenetic mechanisms involved in SAPHO syndrome, etiopathogenesis remains poorly understood. Propionibacterium acnes, the microorganism associated with acne, has been recovered on bone biopsy in some patients, but the possible pathogenetic role of an infectious agent in a genetically predisposed individual, resulting in exaggerated inflammatory response as "reactive osteitis," is a largely unproven hypothesis. The newly available whole-body MRI will assist early diagnosis by detecting multifocal osteitis lesions, some of them asymptomatic, in axial (anterior chest wall, spine, and jaws) and nonaxial sites. Moreover, outcomes are vastly improved by treatment with bisphosphonates and tumor necrosis factor-alpha antagonists.