Peptidomics and genomics analyses were used to study an anti-infection array of peptides of amphibian skin. 372 cDNA sequences of antimicrobial peptides have been characterized from a single individual skin of the frog, Odorrana grahami, encoding 107 novel antimicrobial peptides. This contribution almost triples the number of currently reported amphibian antimicrobial peptides. The peptides can be organized into 30 divergent groups, including 24 novel groups. The diversity in peptide coding cDNA sequences is, to our knowledge, the most extreme yet described for any animal. The patterns of diversification, suggest that point mutations, as well as insertion, deletion, and “shuffling” of oligonucleotide sequences have been responsible. The diversity of antimicrobial peptides may have resulted from the diversity of microorganisms. These diverse peptides exhibit both diverse secondary structure and “host-defense” properties. Such extreme antimicrobial peptide diversity in a single amphibian species is amazing. This makes us have to reconsider the strong capability of innate immunity and molecular genetics of amphibian ecological diversification and doubt the general opinion that 20-30 different antimicrobial peptides can protect an animal because of the relatively wide specificity of the peptide antibiotics. Their antimicrobial mechanisms were investigated. They exert their antimicrobial functions by various means, including forming lamellar mesosome-like structures, peeling off the cell walls, forming pores, and inducing DNA condensation. With respect to the development of antibiotics, these peptides provide potential new templates to further explore.