To enhance infection, enveloped viruses exploit adhesion molecules expressed on the surface of host cells. Specifically, phosphatidylserine (PS) receptors – including members of the human T cell immunoglobulin and mucin domain (TIM)-family – have gained attention for their ability to mediate the entry of many enveloped viruses. However, recent evidence that TIM-1 can restrict viral release reveals a new role for these PS receptors. Additionally, viral factors such as the HIV-1 accessory protein Nef can antagonize this antiviral activity of TIM-1 while host restriction factors such as SERINC5 can enhance it. In this review, we examine the various roles of PS receptors, specifically TIM-family proteins, and the intricate relationship between host and viral factors. Elucidating the multifunctional roles of PS receptors in virus–host interaction is important for understanding viral pathogenesis and developing novel antiviral therapeutics. Many PS receptors serve as cofactors for viral entry.Some PS receptors, such as TIM-1, Axl, and RAGE, restrict viral release.HIV Nef, murine leukemia virus (MLV) glycoGag, and equine infectious anemia virus (EIAV) S2 antagonize TIM-mediated inhibition of viral release, in part through SERINCs.SERINCs potentiate TIM-mediated block of HIV release by stabilizing TIMs.The functional interplay between TIM, SERINC, and Nef may play a role in HIV pathogenesis.