Several variants within membrane-spanning 4-domains subfamily A (MS4A) gene cluster have recently been implicated the association of Alzheimer's disease (AD) by serial recent genome-wide association studies (GWAS). As cell membrane proteins, MS4A family members are found to participate in the regulation of calcium signaling which have been widely discussed in neurodegeneration and AD. Besides, although the MS4A family members are poorly characterized, an important role in immunity has already been identified for several members of this cluster (such as MS4A1, MS4A2, and MS4A4B), indicating the possible involvement of MS4A gene cluster in AD pathogenesis. In this article, we briefly summarize the structure, localization, and function of MS4A gene cluster, review recent genetic and expression findings concerning the association of MS4A gene cluster with AD pathogenesis, and also speculate the possible roles of MS4A gene cluster in this disease. Based on the contributing effects of MS4A gene cluster in AD pathogenesis, targeting MS4A gene cluster might provide new opportunities for AD treatment.