Summary: Human skin and mucosal surfaces are in constant contact with resident and invasive microbes. Recognition of microbial products by receptors of the innate immune system triggers rapid innate defense and transduces signals necessary for initiating and maintaining the adaptive immune responses. Microbial sensing by innate pattern-recognition receptors is not restricted to pathogens. Rather, proper development, function, and maintenance of innate and adaptive immunity rely on continuous recognition of products derived from the microorganisms indigenous to the internal and external surfaces of mammalian host. Tonic immune activation by the resident microbiota governs host susceptibility to intestinal and extra-intestinal infections, including those caused by viruses. This review highlights recent developments in innate viral recognition leading to adaptive immunity, and discusses potential links between viruses, microbiota, and the host immune system. Furthermore, we discuss the possible roles of microbiome in chronic viral infection and pathogenesis of autoimmune disease and speculate on the benefit for probiotic therapies against such diseases.