The problem of drug resistance is very worrying and ever increasing. Resistance is due not only to the reckless use of antibiotics but also to the fact that pathogens are able to adapt to different conditions and develop self-defense mechanisms such as living in biofilms; altogether these issues make the search for alternative drugs a real challenge. Antimicrobial peptides appear as promising alternatives but they have disadvantages that do not make them easily applicable in the medical field; thus many researches look for solutions to overcome the disadvantages and ensure that the advantages can be exploited. This review describes the biofilm characteristics and identifies the key features that antimicrobial peptides should have. Recalcitrant bacterial infections caused by the most obstinate bacterial species should be treated with a strategy to combine conventional peptides functionalized with nano-tools. This approach could effectively disrupt high density infections caused by biofilms. Moreover, the importance of using in vivo non mammalian models for biofilm studies is described. In particular, here we analyze the use of amphibians as a model to substitute the rodent model.