The World Health Organization's (WHO) classification of the central nervous system tumors represented the primary source of diagnosis and grading criteria for the brain tumors. The revision of the WHO classification in 2016 represented a shift from the traditional principle of using neuropathological diagnoses primarily based on the microscopic features, to using molecularly oriented diagnoses. New entities, defined by both the histological and molecular features, such as isocitrate dehydrogenase mutations and 1p/19q co-deletion, were included. To achieve an accurate diagnosis, the selection of suitable genetic testing methods in addition to having a basic knowledge of neuro-oncology and neuropathology, is essential. This text primarily focuses on the differential diagnosis of diffuse small-cell glioma that aids in understanding a practical method for the diagnosis of diffuse gliomas in adults.