Poly(2‐oxazoline)s have excellent biocompatibility and have been used as FDA‐approved indirect food additives. The inert property of the hydrophilic poly(2‐oxazoline)s suggests them as promising substitutes for poly(ethylene glycol) (PEG) in various applications such as anti‐biofouling agents. It was recently reported that poly(2‐oxazoline)s themselves have antimicrobial properties as synthetic mimics of host defense peptides. These studies revealed the bioactive properties of poly(2‐oxazoline)s as a new class of functional peptide mimics, by mimicking host defense peptides to display potent and selective antimicrobial activities against methicillin‐resistant Staphylococcus aureus both in vitro and in vivo, without concerns about antimicrobial resistance. The high structural diversity, facile synthesis, and potent and tunable antimicrobial properties underscore the great potential of poly(2‐oxazoline)s as a class of novel antimicrobial agents in dealing with drug‐resistant microbial infections and antimicrobial resistance.