The CD150 subfamily within the CD2 family is a growing group of dual-function receptors that have within their cytoplasmic tails a characteristic signaling motif. The ITSM (immunoreceptor tyrosine-based switch motif) enables these receptors to bind to and be regulated by small SH2 domain adaptor proteins, including SH2D1A (SH2-containing adaptor protein SH2 domain protein 1A) and EAT-2 (EWS-activated transcript 2). A major signaling pathway through the prototypic receptor in this subfamily, CD150, leads to the activation of interferon-γ, a key cytokine for viral immunity. As a result, many viruses have designed strategies to usurp or alter CD150 functions. Measles virus uses CD150 as a receptor and Molluscum contagiosum virus encodes proteins that are homologous to CD150. Thus, viruses use CD150 subfamily receptors to create a favorable environment to elude detection and destruction. Understanding the CD150 subfamily may lead to new strategies for vaccine development and antiviral therapies.