HIV the pathogen responsible for the transmission of AIDS, which is associated with a high mortality rate. Vpx is expressed in HIV-2/SIV and promotes retroviral infection in specific cells. This promotion is achieved by Vpx-induced formation of the CRL4E3 complex, which removes the endogenous SAMHD1 via proteasomal degradation. Multiple domains of SAMHD1(e.g., N-terminus, nuclear localization signal, linker, HD domain, and C-terminus)are essential for Vpx-induced degradation.HIV-1that does not express Vpx is also evolved with mechanisms to bypass or suppress the antiviral function of SAMHD1,such as the tolerance against a low level of dNTPs and induction of SAMHD1 degradation through cyclin L2.Based on previous reports published chronologically, as well as the latest findings in the field, this review focuses on the mechanism of Vpx-mediated degradation of SAMHD1,and its promotion of HIV-1infection.