Microtubule-associated protein tau (MAPT) is a gene responsible for encoding tau protein, which is tightly implicated in keeping the function of microtubules and axonal transport. Hyperphosphorylated tau protein participates in the formation of neurofibrillary tangles (NFTs), which characterize many neurodegenerative disorders termed tauopathies. Genome-wide association studies (GWAS) have demonstrated numerous single nucleotide polymorphisms (SNPs) located in MAPT associated with various neurodegenerative diseases. Thus, it has been presumed that MAPT plays a crucial role in pathogenesis of neurodegeneration via affecting the structure and function of tau. Here, we review the advanced studies to summarize the biochemical properties of MAPT and its encoded protein, as well as the genetics and epigenetics of MAPT in neurodegeneration. Finally, given the potential mechanisms of MAPT to neurodegeneration pathogenesis, targeting MAPT and tau might present significant treatments of MAPT mutation-related neurodegeneration. Affirmatively, the identification of MAPT is extremely beneficial for improving our understanding of the pathogenesis of various neurodegenerative diseases and developing the mechanism-based therapies.