Mast cells (MCs) are long-lived immune cells. They are armed with preformed mediators within granules that can be instantaneously released in response to an invading pathogen, including certain viruses. At the skin and mucosae, they initiate innate immune responses and promote the development of adaptive immune responses, through cellular recruitment or antigen presentation. However, systemic MC activation may promote immune pathologies through their vasoactive proteases and biogenic amines. Recently, MC products were identified to contribute to pathologies associated with viral hemorrhagic fever, such vascular leakage and thrombocytopenia. Similar associations of MCs with disease severity have been noted for certain respiratory viral pathogens. Here we discuss the specific MC responses to viruses and their influences on functional immune outcomes during infection.