Immunosuppressive domains (ISDs) of viral envelope glycoproteins provide highly pathogenic phenotypes to various retroviruses. The ISD interaction with immune cells leads to an inhibition of the response. As was shown in the 1980s, a 17-amino acid residue of ISD fragment (known as CKS-17) is responsible for this immune modulation. However, the underlying mechanisms were unknown. Thorough research identified activation of signal transduction via the Ras-Raf-MEK-MAPK and PI3K-AKT-mTOR cell pathways as a result of the ISD interaction with immune cells. The result is the decrease in the secretion of stimulatory cytokines (e.g., IL-12) and increase of inhibitory and anti-inflammatory cytokines (e.g., IL-10). One of the receptor tyrosine kinases that triggers signal transduction in these pathways acts as a primary ISD target, while other key regulators, cAMP and diacylglycerol (DAG), act as secondary messengers. Immunosuppressive-like domains are not restricted to retroviruses; an ISD present in Ebola virus envelope glycoproteins determines an extremely severe clinical course of virus-induced hemorrhagic fever. A number of retrovirus-originating ISD-coding regions are found in the human genome. The regions are expressed as parts of the syncytin genes in the placenta, helping to render the mother's immune system tolerant of the placenta and embryo. The review considers the molecular aspects of the retroviral ISD-induced modulation of the host immune system.