Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) often coexist in the same patients: FTLD/MND. However, it is unclear whether FTLD/MND can be distinguished from ALS or FTLD. TAR DNA binding protein 43KDa (TDP-43) has been identified as the major component of the ubiquitin-positive inclusion bodies in ALS, FTLD, and FTLD/MND. On the basis of this finding, a new concept of neurodegenerative disorders, namely TDP-43 proteinopathy, has been proposed for these disorders. In ALS, more than 30 mutations of the TDP-43 gene have been identified. The clinical features and neuropathological findings of ALS with TDP-43 mutation are identical to those of sporadic ALS. Therefore, TDP-43 plays a primary role in the pathogenesis of ALS. In contrast, only few patients with FTLD phenotype have TDP-43 mutations. Therefore, we have speculated that TDP-43 does not play a primary role in the pathogenesis of FTLD. The analysis of distribution of TDP-43 inclusion bodies in ALS patients revealed that ALS has two subtypes: (1) limited in the motor neuron system and (2) extended into the frontotemporal lobe. Additionally, causative genes of familial FTLD/MND have not been mapped to TDP-43. These results suggest that FTLD/MND is a disease distinct from FTLD and ALS.