Many microorganisms including retroviruses suppress the immune system of the infected host in order to maintain infection. Unfortunately, it is still unclear how retroviruses induce immunosuppression. There is increasing evidence of a common mechanism based on their transmembrane envelope proteins. This review therefore summarizes evidence of the involvement of the transmembrane envelope proteins in the immunopathogenesis of different retroviruses including HIV-1. Mutations in the immunosuppressive (isu) domain of the transmembrane envelope protein of several retroviruses abrogate the immunosuppressive activities in vitro and in vivo. Most importantly, virus sequences with such abrogating mutations were never found in HIV-1-infected individuals despite the fact that the mutated viruses are replication-competent. However, there is also evidence for additional, perhaps even divergent, strategies for each retrovirus. For example, in contrast to many other retroviruses, the HIV directly interacts with immune cells and infects them. In addition, HIV uses several accessory proteins to evade the immune response. Furthermore, the possible contribution of the transmembrane envelope proteins of endogenous retroviruses to immunosuppression when expressed on tumor cells or in the placenta is analyzed.