Although Creutzfeldt-Jakob disease (CJD) is the prototypical rapidly progressive dementia, clinical heterogeneity in the disease can make diagnosis difficult. Creutzfeldt-Jakob disease affects multiple brain areas, which causes multifocal deficits that involve movement, cognition, and psychiatric status. Thorough neurologic, cognitive, and psychiatric examinations are necessary for observing its clinical features. Recent advances in neuroimaging techniques have allowed researchers and clinicians to discover imaging patterns that distinguish CJD from other neurologic diseases. This article discusses how these advances may make neuroimaging the most valuable noninvasive tool for diagnosing CJD, which helps to track the progression of the disease course and provides insight into clinical-anatomic correlations.