The increasing frequency of multi-resistant Gram-positive and Gram-negative bacteria and a long-term decreasing trend in the development of new antimicrobial molecules prompts research for new anti-infective agents with new modes of action. Antimicrobial peptides (AMPs) are considered an interesting class of antibacterial molecules. Many new AMPs have been discovered and some are being evaluated for the development of new antibacterial therapeutics. Since the development of new antibacterial drugs has been neglected for decades, we are now faced with extreme medical need combined with a lack of technical experimental progress in setting up efficient models of antibacterial activity in animals. Here we review experiments with AMPs in animal models of sepsis, pneumonia and skin infection caused by bacteria. Animal models of infection have been of enormous predictive value in antibacterial drug discovery, both for elucidating AMP efficacy in the treatment of experimentally induced infection and for comparing the effectiveness of two or more antibiotics.