The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) is unclear. TAR DNA-binding proteins of 43 KDa (TDP-43) immunopositive cytoplasmic inclusions have been found in glia and neurons of ALS patients. The discovery of TDP-43 mutations in ALS patients indicates a direct role of TDP-43 in ALS. More than 30 mutations in the TDP-43 gene have been identified in patients with familial and sporadic ALS. ALS with a TDP-43 mutation is classified as ALS-10. The clinical features of ALS-10 are quite similar to those of sporadic ALS. Furthermore, the neuropathological findings for ALS-10, including TDP-43 immunopositive inclusions and Bunina bodies, are identical to those in sporadic ALS. Most of the mutations are located in the C-terminus of TDP-43, which may function as a binding domain of heterogeneous nuclear ribonucleoprotein. Frontotemporal lobar degeneration: FTLD and FTLD/MND (motor neuron disease) also have TDP-43 immunopositive inclusions. These disorders have been named as TDP-43 proteinopathy. However, patients with TDP-43 mutations rarely develop FTLD. Causative genes for familial FTLD and FTLD/MND are not linked to the TDP-43 gene. Thus, other factors may contribute to the TDP-43 pathology in these diseases. Further analysis is required to elucidate the molecular mechanism of ALS-10 and TDP-43 proteinopathy.