<p>Antimicrobial peptides (AMPs) are endogenous polypeptides produced by multicellular organisms in order to protect a host from pathogenic microbes. AMPs are also defined as host defense peptides because of their essential role in constituting the innate immunity system [1&ndash;4]. AMPs are generally comprised of less than 50 amino acids approximately, and characterized by cationic amphipathic properties. In general, when AMPs are folded in membrane mimetic environments, one side of AMPs is positively charged (mainly due to lysine and arginine residues) and the other side contains a considerable proportion of hydrophobic residues [1,2,5,6]. AMPs show broad-spectrum antimicrobial activities against various microorganisms, including Gram-positive and Gram-negative bacteria, fungi, and viruses [1]. Of particular interest, many AMPs are effective against multi-drug resistan(MDR) bacteria and possess low propensity for developing resistance [7&ndash;9]. Bacterial resistance to antibiotics can be achieved by diverse routes including inhibition of the drug-target interaction, modification of the drug-binding site in target proteins, and efflux of the drug from target cells [10]. Microorganisms can also alter their genetic patterns in response to environmental changes using their own complex systems called sensor-transducer responsesystems. For instance, bacteria can modify their gene expression in the presence of AMPs [11]. AMPs possess low propensity for developing resistance, probably due to their distinguished mode of action. Most AMPs, with their amphipathic nature, directly act on the membrane of the pathogen. The cationic properties of AMPs are implicated in their selective interaction with the negatively chargesurfacesofmicrobialmembranes, resulting in the accumulation of AMPs on the membrane surface. Then, their hydrophobic portions are responsible for the interaction with hydrophobic components of the membrane. From this complex interaction with the membrane, major rearrangements of its structure occur, which may result from the formation of peptide-lipid specific interactions, the peptide translocation across the membrane and interaction with intracellular targets or the most common mechanism, a membranolytic effect [3,11&ndash;16]. Such a characteristic mechanism of action, distinct from that of conventional antibiotics, enables AMPs to avoid the common resistance mechanisms observed for classic antibiotics. Consequently, AMPs are receiving great attention as promising alternatives to conventional antibiotics to overcome the current drug resistance crisis. In this review, we describe the advantages and limitations of AMPs as novel antibiotic agents and structural information aids for developing new AMPs. Especially, we focus on small peptides (less than twelve amino acids in length) in clinical trials and their structure-activity relationships (SAR).</p>