Neuropeptide Y (NPY) and polypeptide YY (PYY) are two ubiquitous neuropeptides, found in brain and intestines, respectively, where they exert important regulatory functions. In this study, a new member of the YY family recently isolated from amphibian skin, skin-PYY (SPYY), is reported to inhibit irreversibly the proliferation of a broad spectrum of pathogenic microorganisms. NPY and PYY are shown to be endowed with the same activity. Their potency is similar to that of other antibacterial peptides which have been shown to exert their function by disintegrating the bacterial membrane. These findings and the fact that the C-terminal alpha-helical domain SPYY14–36, which is highly conserved among the family members, was responsible for killing microorganisms and for permeation of phospholipid vesicles, suggested that the antibiotic activity may emerge via a membrane permeation mechanism. These findings also raise the question whether NPY and PYY exert in vivo a similar function in mammals.