Epidemiologic studies indicate that microbes and microbial components are associated with protection against chronic inflammatory disease. Consequently, a plethora of clinical approaches have been used to investigate the benefits of a range of microbial products on inflammatory conditions in human trials. Centered particularly on the use of prebiotics, probiotic bacteria, and bacterial lysates in early life, this review provides an overview on clinical approaches aimed at reducing the global burden of allergic disease through primary prevention. Microbial interventions beginning before birth and in early infancy are discussed in the context of underlying mechanisms of oral tolerance and the establishment of gut colonization as a critical early homeostatic influence. We explore both the findings and challenges faced in existing studies with a view toward improving future clinical studies of the application of microbial compounds for the prevention of allergic disease and other inflammatory diseases.