Hashimoto's encephalopathy, first described in 1966, is still problematic in terms of its pathophysiology, diagnosis, and treatment. The syndrome is more common in women, and is associated with autoimmune antithyroid antibodies. Presentation varies considerably; there may be episodes of cerebral ischemia, seizure, or psychosis, or there may be depression, cognitive decline, and periods of fluctuating consciousness. Because the symptoms respond so well to immunosuppressive treatment, prompt diagnosis and management are important. Here, the authors present a representative case report, along with a comprehensive review of current literature.