Rapidly progressive dementia is a neurological condition that results in subacute deterioration in cognitive, behavioral and motor function. The most serious diagnosis for a patient with rapidly progressive dementia is Creutzfeldt-Jakob Disease (CJD), a prion-related illness that typically results in death within one year. However, there are numerous autoimmune, infectious and toxic-metabolic causes of rapidly progressive dementia that are potentially reversible with treatment. Thus, the differential diagnosis for a rapidly progressive dementia is critically important. In this article, the authors discuss a case of CJD diagnosed at a St. Paul hospital to illustrate the differential diagnosis of rapidly progressive dementia and highlight the role of neuroimaging.