Host defence peptides (HDPs) are multi-functional inducers and effectors of host immunity. Through their direct antimicrobial activity HDPs have for been successfully utilized for many years as topical antibiotics and food preservatives. The more recent appreciation of HDP immunomodulatory activities offers additional opportunities for application as systemic antimicrobials, anti-inflammatory agents and vaccine adjuvants. HDPs have demonstrated proof-of-principle success in each of these applications. Optimization of HDPs for these objectives will benefit from a greater comprehension of the structural basis of their various activities. Such an understanding will facilitate rational design and/or selection of peptides with enhanced properties. This is complicated, however, by the diversity of HDP sequences, structures and mechanisms of action. Furthermore, while the ability of HDPs to undergo template-driven formation of bioactive structures enables these small peptides to perform a diverse range of actions it also complicates efforts to understand contributions of particular structural features to specific activities. With recognition of these limitations, but consideration of the emerging importance of this exciting class of molecules, we review the current understanding of the structural basis of select HDP activities as well as present strategies for HDP selection and optimization.