The innate immune system of mammals contains a series of peptides with overall positive charge and an amphipathic structure which have a variety of important properties in host defences. Although these are often termed cationic antimicrobial peptides, they have numerous roles in innate defences in all complex species of life and thus we prefer to refer to them as host defence peptides. These roles include: (i) an ability to kill micro-organisms directly, ranging from bacteria to viruses, fungi, parasites and helminths; (ii) an adjuvant activity in the adaptive response; and (iii) a multiplicity of roles in modulating innate immunity, including an apparent ability to stimulate protective innate immunity while suppressing harmful inflammatory/septic responses. This latter property may be one of the more important activities of these peptides in vivo. Innate immunity is thought to be triggered by the interaction of conserved bacterial components with particular receptors including Toll-like receptors (TLRs) on host cells. However, the initiation of the innate immune response through this route may trigger a pro-inflammatory cascade that is the principle cause of harmful conditions such as sepsis. Since we are exposed to potentially dangerous pathogens on a daily basis, the host response must contain certain checks and balances. We propose that host defence peptides have a role in feed-back modulation of inflammation under normal (low-pathogen exposure) conditions. This review surveys the available information regarding the anti-endotoxic/anti-inflammatory properties of host defence peptides, and will address whether this potential might be exploited for therapeutic benefit in sepsis.