Antimicrobial peptides (AMPs) offer promise as complements to conventional small-molecule antibiotics, as bacteria have been unable to evolve resistance to AMPs over the course of natural history. However, since peptide therapeutics have poor bioavailability and are potentially immunogenic, they are considered of limited promise as antimicrobial drugs. To circumvent these undesirable characteristics, we are developing a new class of antimicrobial peptide mimic based on sequence- and length-specific oligo-N-substituted glycines; we call these AMP analogs “ampetoids”. Some of these helical, biomimetic oligomers are as potent and selective as their natural peptide counterparts (e.g., magainin-2), and have broad-spectrum antibacterial activity and MICs in the high-nanomolar to low-micromolar range. Studies of ampetoid structure-activity relationships strongly suggest that these structured oligomers behave analogously to AMPs, employing membrane permeabilization mechanisms consistent with the barrel-stave/carpet paradigm. This implies that, like AMPs, ampetoids are far less susceptible to the development of bacterial resistance than are conventional antibiotics. Biophysical studies, such as calcein leakage from large unilamellar vesicles and X-ray scattering substantiate this hypothesis, suggesting that lipid bilayer disruption is integral to ampetoids' bacterial killing mechanism. However, our results also demonstrate that interactions with the cytoplasmic membrane are not the sole determinant of ampetoid activity; inter-peptoid associations and interactions with other cell constituents, such as outer membranes or cell walls, are important as well. The toxicity of some of our most potent oligomers to human red blood cells and epithelial cells is minimal.