Based on the cerebral tans‐activation response DNA protein 43 (TDP‐43) immunohistochemistry, frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP) is classified into four subtypes: type A has numerous neuronal cytoplasmic inclusions (NCIs) and dystrophic neurites (DNs); type B has numerous NCIs with few DNs; type C is characterized by DNs which are often longer and thicker than DNs in type A, with few NCIs; and type D has numerous neuronal intranuclear inclusions and DNs with few NCIs. The relevance of this classification system is supported by clinical, biochemical and genetic correlations, although there is still significant heterogeneity, especially in cases with type A pathology. The subtypes of TDP‐43 pathology should be determined in cases with other neurodegenerative disorders, including Alzheimer's disease and dementia with Lewy bodies, to evaluate the pathological significance of TDP‐43 abnormality in them. The results of the biochemical analyses of the diseased brains and the cellular models suggest that different strains of TDP‐43 with different conformations may determine the clinicopathological phenotypes of TDP‐43 proteinopathy, like prion disease. Clarifying the mechanism of the conformational changes of TDP‐43 leading to the formation of multiple abnormal strains may be important for differential diagnosis and developing disease‐modifying therapy for TDP‐43 proteinopathy.