OBJECTIVE: We aim to demonstrate the versatility of the All of Us database as an important source of rare and undiagnosed disease (RUD) data, because of its large size and range of data types. MATERIALS AND METHODS: We searched the public data browser, electronic health record (EHR), and several surveys to investigate the prevalence, mental health, healthcare access, and other data of select RUDs. RESULTS: Several RUDs have participants in All of Us [eg, 75 of 100 rare infectious diseases (RIDs)]. We generated health-related data for undiagnosed, sickle cell disease (SCD), cystic fibrosis (CF), and infectious (2 diseases) and chronic (4 diseases) disease pools. CONCLUSION: Our results highlight the potential value of All of Us with both data breadth and depth to help identify possible solutions for shared and disease-specific biomedical and other problems such as healthcare access, thus enhancing diagnosis, treatment, prevention, and support for the RUD community.