Autophagy is a cell biological process that promotes resilience in the face of environmental perturbations. Given that infectious agents represent a major type of environmental threat, it follows that the autophagy pathway is central to the outcome of host-microbe interactions. Detailed molecular studies have revealed intricate ways in which autophagy suppresses or enhances the fitness of infectious agents, particularly intracellular pathogens such as viruses that require the host cell machinery for replication. Findings in animal models have reinforced the importance of these events that occur within individual cells and have extended the role of autophagy to extracellular microbes and immunity at the whole organism level. These functions impact adaptation to bacteria that are part of the gut microbiota, which has implications for the etiology of chronic disorders such as inflammatory bowel disease. Despite major advances in how autophagy regulates inflammatory reactions toward microbes, many challenges remain, including distinguishing autophagy from closely related pathways such as LC3-associated phagocytosis. Here, we review the role of autophagy in microbial pathogenesis at the level of organismal biology. In addition to providing an overview of the prominent function of autophagy proteins in host-microbe interactions, we highlight how observations at the cellular level are informing pathogenesis studies and offer our perspective on the future directions of the field.