TAR DNA binding protein (TDP-43) and Fused in Sarcoma (FUS) are predominantly nuclear proteins that regulate gene transcription, splicing and transport. They are also involved in micro-RNA biogenesis. TDP-43 is the major protein component of cytoplasmic inclusions in fronto-temporal lobar dementia (FTLD-TDP-43) and amyotrophic lateral sclerosis (ALS) while FUS is deposited in a small number of MAP tau and TDP-43 negative FTLD cases. Mutations in the genes encoding TARDBP and FUS are detected in 1-4% of familial ALS cases and are also seen in ~1% of sporadic ALS cases. TDP-43 and FUS mutant proteins show reduced nuclear import and are neurotoxic strongly implicating mislocalisation in the pathogenesis of ALS and FTD. Mutations are not detected in the vast majority of ALS and FTLD cases in which these proteins are deposited. Thus the mechanisms involved in regulating the nuclear import or cytoplasmic degradation may be important in the pathogenesis of these disorders.