Platelets have emerged as an important factor in viral infections. As prevalent surveyors of the vascular space, platelets associate with a wide range of viruses, both directly and by immune complex sensing, because they are endowed with pathogen response receptors and numerous recognized pathogen-attachment receptors. Once a platelet-virus interaction occurs, the platelet is activated and undergoes many functional changes consistent with its physiological roles in host defense and hemostasis. The consequence is that local endothelial cells, leukocytes, and neutrophils are stimulated due to the release of platelet granule contents and the exposure of a procoagulant surface contributing to thrombin production. Thrombin not only generates clots to restrict the pathogen from disseminating through the vasculature but also contributes to further activation of platelets and other inflammatory cells. Induction of phagocytosis by leukocytes and neutrophil extracellular trap formation contributes to pathogen clearance. In addition to these innate immune responses, platelets have the appropriate biological machinery to phagocytose the pathogen and process it in major histocompatibility complex pathways to provoke an adaptive immune response. However, the platelet-virus interaction may have both positive and detrimental impacts on the health of the infected host when infection induces dysfunction. Thrombocytopenia, disseminated intravascular coagulation, thrombosis, and platelet-dependent inflammation may result as pathophysiological responses to virus-induced amplification of “normal” platelet roles in hemostasis and host defense.