Drs. Kataria and Vaughn explain the pathophysiology and treatment of this circadian rhythm sleep disorder. Irregular sleep-wake rhythm disorder (ISWRD) is characterized by the absence of circadian synchronization with an individual’s sleep-wake cycle. Irregular sleep-wake rhythm disorder is typically seen in patients with neurodegenerative disorders such as Alzheimer disease and dementia, and it is seen in institutionalized elderly patients; however, it has been also observed in patients with traumatic brain injury and neurodevelopmental disorders. Increased exposure to circadian zeitgebers, such as bright light and structured activities, may minimize the disturbance. Pharmacologic therapy with melatonin was generally ineffective in randomized control trials despite encouraging open studies in small series of pediatric patients thought to have irregular sleep-wake rhythm disorder. This review enables basic understanding of the circadian clock biology and its interactions with the sleep-wake cycle.