Host defense peptides (HDPs) are important in defense of tissues throughout the human mouth. Like resident microbial populations, HDPs are diverse, species-specific, and site-specific, and they have evolved in response to selection pressures exerted by resident and pathogenic microbial populations. Their site-specific expression is likely to be a significant contributor to the tissue tropism displayed by microorganisms throughout the body. Currently there is an impetus to understand host–microbe interactions in health as well as disease, and the mechanisms underlying the ability of host tissues to tolerate resident microbial populations while maintaining efficient responses to pathogens are of fundamental importance. No consistent correlation has emerged so far between oral commensalism and susceptibility to, or induction of HDPs. Equally; pathogenic bacteria exhibit a variety of strategies for evading or surviving HDPs. However, only a small number of oral commensal species and strains have been studied. Also, to truly understand the in vivo roles of HDPs in health and protection against infection one needs to understand their interactions with organisms in complex biofilm communities, not with planktonic monocultures as has predominantly been the case to date.