Synthetic polymers have been used as a molecular platform to develop host-defense antimicrobial peptide (AMP) mimics toward the development of “polymer antibiotics” which are effective in killing drug-resistant bacteria. Our research has been centered on the AMP-mimetic design and chemical optimization strategies as well as the biological and biophysical implications of AMP mimicry by synthetic polymers. The AMP-mimetic polymers showed broad-spectrum activity, rapid bactericidal activity, and low propensity for resistance development in bacteria, which represent the hallmarks of AMPs. The polymers form amphipathic conformations capable of membrane disruption upon binding to bacterial membrane, which recapitulates the folding of alpha-helical AMPs. We propose a new perception that AMP-mimetic polymers are an inherently bioactive platform as whole molecules, which mimic more than the side chain functionalities of AMPs. The chemical and structural diversity of polymers will expand the possibilities for new antimicrobial materials including macromolecules and molecular assemblies with tailored activity. This type of synthetic polymers is cost-effective, suitable for large-scale production, and tunable for diverse applications, providing great potential for the development of versatile platforms that can be used as direct therapeutics or attached on surfaces.