Frontotemporal lobar degeneration (FTLD) is a clinical syndrome characterized by behavioral and language difficulties,which refers to a clinically, genetically, and neuropathologically heterogeneous group of neurodegenerative disorders. Familial FTLD has been linked to mutations in several genes : the microtubule-associated protein tau (MAPT), progranulin (GRN), valosin-containing protein (VCP) and charged multivescicular body protein 2B (CHMP2B), and genetic locus on chromosome 9p linked to familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The associated neuropathology is characterized by selective degeneration of the frontal and temporal lobes with the neuronal and/or glial inclusions. The current classification of FTLD neuropathology is based on the major constituent protein of them : tau,TAR DNA-binding protein of 43 kD (TDP-43), and fused in sarcoma (FUS). Abnormal phosphorylation,ubiquitination,and proteolytic cleavage are the common pathologic signature of tau and TDP-43 accumulated in diseased brains. Recent findings of TDP-43 and FUS reveal that FTLD and ALS share a common mechanism of pathogenesis. This review focuses on the current understanding of the molecular neuropathology of FTLD, and their relevance to the development of the therapeutics