Gene testing in primary immune deficiencies (PIDs) once was limited to expert academic laboratories, but now is easily available to physicians with a broad range of clinical expertise. Such testing can establish or confirm a suspected diagnosis and also may predict future disease risk in advance of clinical signs and symptoms, inform reproductive decision making, and guide clinicians in selecting the most appropriate therapeutic options. This article, based on the authors' experience and a review of the published literature, discusses some of the advances and challenges currently encountered in the clinical molecular genetic diagnosis of PIDs.