Antimicrobial peptides (AMPs) represent an ancient group of molecules with diverse functions in innate immunity. To date, more than 1000 naturally-occurring AMPs have been identified which display considerable diversity in their primary sequences, lengths, structures and biological activities. Despite this variability, AMPs are broadly classified according to homologous secondary structures as cathelicidins (linear a-helical peptides), defensins (ß-strand peptides connected by disulfide bonds) and bactenecins (loop peptides). Most, but not all, AMPs are cationic with amphipathic faces. These biochemical properties bestow many peptides with potent antimicrobial activity by facilitating interactions with negatively charged microbial cell membrane components, thereby increasing membrane permeability and resulting in microbial death. Other indirect effects on microbial physiology have been reported including inhibition of DNA/RNA synthesis, impaired protein synthesis and folding, disruption of cell wall formation and inhibition of microbial cell metabolism. Thus, with the spread of antibiotic-resistant microbial pathogens, AMPs have emerged as exciting candidates for next generation anti-infective therapies. However, recent studies suggest that AMPs have evolved other mechanisms of pathogen clearance. Immunomodulation is a novel approach to antimicrobial therapy that centres on boosting host immunity rather than direct microbial killing. This is also an attractive means to treat sepsis and other immune-mediated diseases. Whilst several cationic peptides are under investigation as antimicrobial agents, a select few show a remarkable ability to protect against lethal endotoxaemia and clinically-relevant bacterial infections including methicillin-resistant Staphylococcus aureus (MRSA). The molecular mechanisms responsible for this protection are only beginning to emerge but include prevention of innate cell activation by targeting key stages of bacterial endotoxin-mediated cell signalling. In this research topic, hosted by Frontiers in Molecular Innate Immunity, we aim to highlight key areas of AMP research including peptide diversity, structure-function relationships, antimicrobial activity and mechanisms of immune-modulation. We also aim to stimulate discussion on the emerging therapeutic potential of AMPs including antifungal, antiviral and anticancer applications.