Efforts to generate antibacterial agents via mimicry of host-defense peptides have focused on discrete oligomers that can adopt a regular globally amphiphilic conformation in the presence of bacterial cell membranes and ultimately disrupt those membranes. Although considerable success has been achieved with this approach, application of the resulting molecules is hampered by the high cost associated with stepwise oligomer synthesis. We show that random poly-beta-peptide copolymers, prepared by ring-opening polymerization of beta-lactams, can be tuned to display good activity against a panel of four bacteria along with low lytic activity toward human red blood cells. These findings support a nonclassical design hypothesis for antibacterial agents.