The　proliferation　and　global　expansion　of　multidrug-resistant　(MDR)　bacteria　have　deepened　the　need　to　develop　novel　antimicrobials.　Antimicrobial　peptides　(AMPs)　are　regarded　as　promising　antibacterial　agents　because　of　their　broad-spectrum　antibacterial　activity　and　multifaceted　mechanisms　of　action　with　non-specific　targets.　However,　if　AMPs　are　to　be　applied　sustainably,　knowledge　of　how　they　induce　resistance　in　pathogenic　bacteria　must　be　mastered　to　avoid　repeating　the　traditional　antibiotic　resistance　mistakes　currently　faced.　Furthermore,　the　evolutionary　constraints　on　the　acquisition　of　AMP　resistance　by　microorganisms　in　the　natural　environment,　such　as　functional　compatibility　and　fitness　trade-offs,　inform　the　translational　application　of　AMPs.　Consequently,　the　shortcut　to　achieve　sustainable　utilization　of　AMPs　is　to　uncover　the　evolutionary　constraints　of　bacteria　on　AMP　resistance　in　nature　and　find　the　tricks　to　exploit　these　constraints,　such　as　applying　AMP　cocktails　to　minimize　the　efficacy　of　selection　for　resistance　or　combining　nanomaterials　to　maximize　the　costs　of　AMP　resistance.　Altogether,　this　review　dissects　the　benefits,　challenges,　and　opportunities　of　utilizing　AMPs　against　disease-causing　bacteria,　and　highlights　the　use　of　AMP　cocktails　or　nanomaterials　to　proactively　address　potential　AMP　resistance　crises　in　the　future.　©　2022　Elsevier　Inc.