Asthma is a disorder of increasing prevalence and severity that has been linked with reduced early-life exposure to microbes and microbial products. Populations with increased environmental exposures to pathogen-associated molecular patterns (e.g., children who have large numbers of older siblings, who were raised on farms, and who have earlier out-of-home day-care attendance) have fewer and less severe atopic disorders. The mechanism(s) responsible for these observations remain uncertain, but modulation by pathogen-associated molecular patterns of the inflammatory milieu (and thus the setting in which allergens may be encountered) has received strong support. One microbial product with marked immunostimulatory properties is bacterial DNA, which differs from mammalian DNA in the frequency of cytosine-guanine (CpG) dinucleotides; many of the effects of bacterial DNA can be recapitulated by oligodeoxynucleotides (ODNs) containing CpG in specific base sequence motifs (CpG ODNs). Because CpG ODNs induce Th1-type cytokines (which can suppress the Th2-type responses that cause many of the manifestations of allergic disease), we speculated that they may be useful in preventing or reversing the eosinophilic inflammation of atopic asthma. We found this to be the case, using murine models of incipient and established allergic asthma, but learned that the Th1-type cytokines were not critical for efficacy. Subsequent work has suggested that induction of regulatory-type responses (from T cells and antigen-presenting cells) is involved in the protection provided by CpG ODNs. Ongoing clinical trials are examining the utility of CpG ODNs alone and as an adjuvant for immunotherapy in human populations with atopic disease.