Extraocular muscle involvement in orbital disease is most frequently seen as a feature of thyroid orbitopathy (Graves' disease). However, a wide range of other conditions may alter the size, shape, and function of these muscles, with characteristic clinical manifestations or abnormalities visible on orbital imaging. The differential diagnosis of muscle disease can be narrowed by careful analysis of clinical features and ancillary tests. Imaging facilitates recognition in many cases, but in some instances, accurate diagnosis requires biopsy. This review highlights the differential diagnoses for diseases of extraocular muscles based on the clinical and investigative records of 103 patients at our institution combined with data from the world literature. We found that the most common nonthyroid causes of muscle disease were inflammatory, vascular, and neoplastic processes (in decreasing order of frequency). Emphasis is placed on investigations that provide a logical approach to, and appropriate management of, disease of the extraocular muscles.