<p>Creutzfeldt–Jakob disease (CJD) is a classic member of the group of prion diseases and is characterized by progressive degeneration of nervous system structures with a variety of neurological symptoms, steady progression, and inevitable death. The disease arises from a change in the tertiary structure of a protein, which leads to disruption of the normal functioning of cells. Despite the fact that the etiology and pathogenesis of CJD have now been well studied, the in-life diagnosis of this severe disease remains difficult because of the characteristics of the pathological process (unusually long incubation period, diversity of clinical symptoms), the absence of pathognomonic markers for high-reliability diagnosis, and insufficient awareness on the part of health workers. At the same time, differential diagnosis of the disease to exclude potentially curable conditions remains relevant. This review analyzes data on CJD, starting from the description of the first cases of the disease in the first half of the 20th century to modern diagnostic criteria, with an emphasis on the in-life diagnosis of CJD, with a detailed description of instrumented methods, i.e., electroencephalography and brain MRI scans. We also present a clinical case which allows us to address the possibility of making correct diagnoses in the neurological department of a multidisciplinary medical institution. Despite the fact that effective treatment for CJD has not yet been developed, correct diagnosis is extremely important, as the unique resistance of prions to traditional methods of cleaning instruments and the possibility of iatrogenic transmission require increased attention to the disinfection procedure and determine the need for strict accounting of all cases of this disease.</p>