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Microbial infections endanger human health and life. Conventional antibiotics has saved countless human lives, however, is seriously challenged by the quick emergence of antibiotic-resistant pathogens. It is urgent to develop new types of antimicrobial agents to treat antibiotic-resistant microbial infections. Host defense peptides (HDPs) have broad-spectrum antimicrobial activity and low susceptibility to antimicrobial resistance, therefore, have been actively studied to develop promising antimicrobial agents. However, natural HDPs are structurally unstable due to their easy hydrolysis by proteases. Sequence-defined peptides have been explored as HDP mimics and have proven as promising candidates of antimicrobial drugs. Nevertheless, preparation of these HDP-mimicking peptides by solid-phase synthesis is time-consuming, expensive, and difficult for large scale synthesis. Assisted by the development of polymerization chemistry, polypeptides can be prepared in the form of amino acid polymers conveniently and at large scales using the polymerization strategy. Amino acid polymers, also known as poly(amino acid)s, have the same or similar backbone structure as natural peptides and have excellent biocompatibility. Several classes of such antimicrobial polymers have been explored as synthetic mimics of HDPs including α-amino acid polymers, β-amino acid polymers, peptoid polymers, amino acid hybrid polymers, and peptide mimicking polymers such as poly(2-oxazoline)s. To tune the biological activities and obtain the optimal antimicrobial polymers, key structure characteristics of HDPs are involved and investigated such as positive charges and the hydrophobic/hydrophilic amphiphilic structure. In this review, we provide an overview of research in the last decade about the design of HDP-mimicking antimicrobial amino acid polymers and beyond, including positive charge, amphiphilic structure, chain length, end group, hydrophilicity, stereochemistry, secondary structure, topology, self-assembly and backbone structure, as well as the major applications of antimicrobial amino acid polymers. Finally, we provide a perspective on the comparison between antimicrobial peptides and antimicrobial amino acid polymers, as well as some key challenges that still need to be addressed for possible clinical application of HDP-mimicking antimicrobial amino acid polymers. [Display omitted] [ABSTRACT FROM AUTHOR]