4The tetraspanins are a broadly expressed superfamily of transmembrane glycoproteins with over 30 members found in humans and with homologues conserved through distantly related species, including insects, sponges, and fungi. Members of this family appear to form large integrated signaling complexes or tetraspanin-enriched microdomains (TEMs) by their association with a variety of transmembrane and intracellular signaling/cytoskeletal proteins (49). These interactions link tetraspanins to an array of physiological functions and, in consequence, to numerous endogenous pathologies, including cancer development and inherited disorders (Table 1).Tetraspanins are also known to have roles in the pathology of infectious diseases such as diphtheria, malaria, and numerous viral infections (Table 1). The literature currently indicates that specific tetraspanin family members are selectively associated with specific viruses and affect multiple stages of infectivity, from initial cellular attachment to syncytium formation and viral particle release. Thus, the relationship of tetraspanins with viruses appears to be particularly complex.Here, we will consider this data in the context of recent developments in tetraspanin biology, particularly in our understanding of the architecture and function of TEMs. With the benefit of recent insights into tetraspanin function in cell fusion events and intracellular trafficking, we discuss common features of tetraspanin/viral associations which indicate a fundamental role for TEMs in a number of viral infections. We will also consider the existing therapeutic strategies for human immunodeficiency virus (HIV), hepatitis C virus (HCV), and human T-cell lymphotropic virus type 1 (HTLV-1), focusing on the potential therapeutic value of targeting TEMs, using peptide reagents based on tetraspanin extracellular regions.