Several animal models have been developed recently to study Clostridium perfringens intestinal diseases of animals and humans. Examples of these models include: i) Ligated intestinal loops of rabbits to study the synergistic effects of C. perfringens enterotoxin (CPE) and beta toxin (CPB). Human enteritis necroticans strain CN3758, carry both the cpb and the cpe genes. We evaluated the possibility that CPB and CPE might act together in the intestine by preparing isogenic cpb or cpe null mutants of CN3758. When sporulating culture lysates (SCL) of those strains were tested in rabbit small intestinal loops, wild-type CN3758 SCL induced necrotizing lesions and fluid accumulation. Loops treated with SCL from either the cpb or cpe null mutant, developed no damage. Complementation of the cpe mutant, or reversal of the cpb mutation, restored the ability to damage rabbit small intestinal loops. These results indicate that CPB and CPE can work together in vivo, providing the first evidence for synergistic toxin interactions for C. perfringens enteric disease. ii) The use of a Claudin-4 derivative to protect against C. perfringens CPE. C. perfringens CPE action starts when this toxin binds to a claudin receptor. Claudins are transmembrane proteins that contain two extracellular loop domains. CPE has been shown to bind to the second claudin-4 extracellular loop (ECL-2). We evaluated whether a synthetic peptide with the claudin ECL-2 sequence can inhibit CPE action in a rabbit small intestinal loop assay. Pre-incubation or co-incubation of CPE with claudin-4 ECL-2 peptide inhibited the development of CPE-induced fluid accumulation and histologic lesions in rabbit small intestinal loops. Claudin-4 ECL-2 peptides should be further investigated for their potential therapeutic application against CPE-associated disease. Overall, our studies indicate the importance of combining genetic studies and the use of animal disease models to study the pathogenesis of diseases produced by C. perfringens.