DNA viruses frequently activate a cellular mitogenic response at the outset of infection that poises the cell for the replication of the viral genome once it reaches the nucleus. Endocytic transport and signal transduction are increasingly being appreciated as tightly coupled events. Thus, the initial interactions of the virus with the cell surface, as well as during entry, are critical for maximizing virus yields. Polyomaviruses induce typical early (serum) response genes (i.e., c-myc, c-fos) upon cell attachment, and via their VP1 capsid protein bind well-characterized ganglioside receptors, which may be involved in initiating the signal transduction cascade. Although many viruses interact with cell surface glycan/ganglioside receptors, the use of lipid-based signaling mechanisms during cell entry may play critical and underappreciated roles in viral pathogenesis. Using cells deficient in glycolipid modifications and ligands with specific capsid protein mutations affecting glycan and integrin binding we will characterize the transcriptional signals induced during polyomavirus attachment and entry. These studies of VP1 signaling may uncover intracellular signaling pathways that are critical to viruses engaging sequential receptors during infection. For example, SV40/BKV/JCV infections are blocked by the non-specific tyrosine kinase inhibitor genistein, suggesting that identifying more specific signaling targets could lead to the development of small molecule inhibitors of polyomavirus infection. Although potentially very significant for the therapy of human BKV and JCV infections in immunocompromised individuals, additional targets may be identified that extend beyond the polyomaviruses to the many other viruses that use sialyl-glycans as attachment proteins, opening new avenues for anti-viral therapy.