Goblet cells are specialized epithelial cells that are essential to the formation of the mucus barriers in the airways and intestines. Armed with an arsenal of defenses, goblet cells can rapidly respond to infection but must balance this response with maintaining homeostasis. Whereas goblet cell defenses against bacterial and parasitic infections have been characterized, we are just beginning to understand their responses to viral infections. Here, we outline what is known about the enteric and respiratory viruses that target goblet cells, the direct and bystander effects caused by viral infection and how viral interactions with the mucus barrier can alter the course of infection. Together, these factors can play a significant role in driving viral pathogenesis and disease outcomes.