Small, cysteine-rich, beta-sheet peptide antibiotics are found throughout the Animalia. Though broad spectrum in potential, they may exert selective antimicrobial effects under certain conditions. We have explored the antimicrobial properties of two families of beta-sheet peptide antibiotics, defensins and protegrins, against periodontopathic bacteria. The rabbit defensin NP-1 was active against facultative Gram-negative bacteria associated with early onset periodontitis, including Actinobacillus actinomycetemcomitans and the Capnocytophaga spp. Porcine protegrins showed even greater activity against those organisms, as well as against anaerobic bacteria associated with adult periodontitis, including Porphyromonas gingivalis Prevotella intermedia and Fusobacterium nucleatum. Based on these observations, we believe that protegrin-like beta-sheet peptide antibiotics may be useful dental therapeutics.