Host defense peptides (HDPs) are positively-charged and amphipathic components of the innate immune system that have demonstrated great potential to become the next generation of broad spectrum therapeutic agents effective against a vast array of pathogens and tumor. As such, many approaches have been taken to improve the therapeutic efficacy of HDPs. Amongst these methods, the incorporation of ᴅ-amino acids (ᴅ-AA) is an approach that has demonstrated consistent success in improving HDPs. Although, virtually all HDP review articles briefly mentioned about the role of ᴅ-AA, however it is rather surprising that no systematic review specifically dedicated to this topic exists. Given the impact that ᴅ-AA incorporation has on HDPs, this review aims to fill that void with a systematic discussion of the impact of ᴅ-AA on HDPs.