BACKGROUND: Rapidly progressive dementia (RPD) is a unique set of disorders resulting in cognitive, behavioral, and motor decline within 2 years. A variety of etiologies may contribute to RPD including neurodegenerative, inflammatory, infectious, and toxic-metabolic conditions. Jakob-Creutzfeldt disease (CJD) is frequently the most concerning diagnosis on the differential. The challenge for the neurologist is distinguishing prion disease from reversible processes that result in dementia. REVIEW SUMMARY: This review discusses the clinical aspects and the diagnostic workup of RPD. Particular focus is given to both CJD and the potentially treatable inflammatory conditions that may cause a similar presentation. Furthermore, a standardized stepwise approach is outlined for patients presenting with RPD. CONCLUSIONS: Neurologists should adopt a standardized approach to the rapidly presenting disease processes that may mimic CJD in their clinical and radiologic features.