Wolfram syndrome is a rare, autosomal recessive syndromic diabetes mellitus, most commonly caused by pathogenic variants in the WFS1 gene. Less frequently, pathogenic variants in the CISD2 are responsible. Wolfram syndrome is clinically defined by the presence of diabetes mellitus, optic nerve atrophy, progressive neurologic decline, and, in many patients, arginine vasopressin deficiency, sensorineural hearing loss, neurogenic bladder, and anxiety. As no approved therapies currently exist to modify the disease course, timely diagnosis and coordinated, multidisciplinary care are critical.