Glycosphingolipids (GSLs) are components of the cell membrane that comprise a membrane bound lipid, ceramide, coupled to an extracellular carbohydrate. GSLs impact numerous aspects of membrane biology, including membrane fluidity, curvature, and organization. The role of these molecules in both chronic inflammation and infectious disease and underlying pathogenic mechanisms are just starting to be recognized. As a component of the cell membrane, GSLs are also incorporated into lipid bilayers of diverse enveloped viruses as they bud out from the host cell and can go on to have a significant influence on viral pathogenesis. Dendritic cell (DC) subsets located in the peripheral mucosal tissues are proposed to be one of the earliest cell types that encounter transmitted viruses and help initiate adaptive immune responses against the invading pathogen by interacting with T cells. In turn, viruses, as obligatory intracellular parasites, rely on host cells for completing their replication cycle, and not surprisingly, HIV has evolved to exploit DC biology for the initial transmission event as well as for its dissemination and propagation within the infected host. In this review, we describe the mechanisms by which GSLs impact DC-mediated HIV trans-infection by either modulating virus infectivity, serving as a direct virus particle-associated host-derived ligand for specific interactions with DCs, or modulating the T cell membrane in such a way as to impact viral entry and thereby productive infection of CD4(+) T cells.