There is currently a threat posed by the rapid emergence of antibiotic-resistant pathogens due to the abuse of conventional antibiotics. To overcome such a resistance problem, it is necessary to develop peptide agents with potent antimicrobial activities and high selectivity for target bacterial strains. Conventional approaches, such as the deletion, addition, and replacement of amino acid residues in the template peptide have been employed to alter the properties of antimicrobial peptides (AMPs). In this review, we summarize a recently developed approach, chemical modification, for the improvement of various types of naturally-occurring AMPs. By applying this design strategy to these peptide sequences, new AMPs with enhanced antimicrobial activities and improved selectivity for microorganisms have been successfully generated. This potential strategy should facilitate the creation of novel class of peptide antibiotics with properties suitable for pharmaceutical application.