Alzheimer's disease (AD) is the most common type of neurodegenerative disorder. Mounting evidence suggests that genetic factors play a crucial role in the pathogenesis of AD. The triggering receptor expressed on myeloid cells 2 (TREM2) gene is a recently identified susceptibility gene for AD. Here, we comprehensively reviewed our previous findings and the recent high-quality studies regarding 1) the association of TREM2 variants with AD risk, 2) the structure, ligand and downstream signaling of TREM2, 3) the involvement of TREM2 in AD progression, 4) targeting TREM2 for AD treatment. This review will offer further insights into the genetic and pathogenic mechanisms of AD, and provides reference for the development of novel AD therapies.