Seventeen years have passed since the first report of the synthesis of peptides with antimicrobial activity in the skin of African clawed frog, Xenopus laevis. Since that time more than 200 such peptides have been isolated from the skins of other frogs belonging to different families. With very few exceptions, the frog skin antimicrobial peptides are cationic, relatively hydrophobic and have the propensity to form an amphipathic α-helix in a membrane-mimetic environment. By making selective changes to the molecular charge, hydrophobicity and secondary structure of the naturally occurring peptides, analogues have been developed that show increased potency against microorganisms but reduced toxicity towards mammalian cells. Because of their non-specific mechanism of producing cell death, pathogens develop resistance to the antimicrobial peptides at much lower rates than to conventional antibiotics. The magainins, dermaseptins, ranalexin, brevinins, ranatuerin-1 and buforin-2 (and their analogues) have received particular attention with regard to possible clinical applications. However, despite showing broad-spectrum activity against strains of antibiotic-resistant bacteria and potent activity against certain pathogenic fungi and protozoa, their therapeutic potential remains to be realized. No anti-infective peptide based upon their structures has yet been adopted in clinical practice. New clinical applications need to be found if progress in the field is to continue.