Objective: In July 2017 a multidisciplinary clinical Center specialized in rare diseases was activated. A rare disease can involve the musculoskeletal system. A multimodality musculoskeletal imaging approach allows for a rapid diagnosis. The purpose of this study was to assess when musculoskeletal radiology, ultrasound in particular, plays a primary role in the diagnostic path of a rare disease. Methods and materials: The Center included a list of 621 main rare diseases. Pathologies in which radiology has a primary diagnostic role were extracted from the list. From September 2017 to January 2018 all conditions involving the musculoskeletal system, including the peripheral nervous system, were systematically evaluated by one radiologist. The second radiologist, an official consultant of the Center, verified the list for consistency. Descriptive analysis was performed. Results: A total of 101/621 (16%) rare diseases can be diagnosed for the first time in the diagnostic path of the patient with medical imaging. A total of 36/101 (36%) rare diseases involve the musculoskeletal system. A total of 14/36 (39%) are pediatric diseases, 10/36 (28%) are adult age diseases, while 12/36 (33%) diseases affect all ages. A total of 23/36 (64%) of the selected rare diseases could be diagnosed with MRI, 19/36 (53%) with CT, 23/36 (64%) with X-ray, 9/36 (25%) with an US, and 1/36 (3%) with PET. Conclusions: Musculoskeletal imaging could be important for a noninvasive diagnosis in up to 36/101 (36%) rare diseases, as well as for outcome prediction, especially in pediatrics. Musculoskeletal imaging plays a crucial role in the diagnosis of rare diseases and could strongly influence the clinical pathway. Ultrasound