Adaptive antibody responses provide a crucial means of host defense against viral infections by mediating the neutralization and killing infectious pathogens. At the forefront of humoral defense against viruses lie a subset of innate-like serum antibodies known as natural antibodies (NAbs). NAbs serve multifaceted functions in host defense and play an essential role in early immune responses against viruses. However, there remain many unanswered questions with regard to both the breadth of viral antigens recognized by NAbs, and how B cell ontology and individual antigenic histories intersect to control the development and function of antiviral human NAbs. In the following article we briefly review the current understanding of the functions and source of NAbs in the immune repertoire, their role during antiviral immune responses, the factors influencing the maturation of the NAb repertoire, and finally, the gaps and future research needed to advance our understanding of innate-like B cell biology for the purpose of harnessing NAbs for host defense against viral infections.