Small-molecule-mediated disruption of bacterial membranes is an important component of the innate immune response in numerous organisms including humans. Although still under-represented in the clinically used repertoire of antibiotics, several antimicrobial agents that act by disrupting the structures and functions of bacterial membranes are used for treatment of topical and internal infections. Due to the relatively conserved structure compositions of bacterial membranes, antibiotics that disrupt bacterial membranes should be less likely to induce drug resistance than antibiotics that target other bacterial systems. However, drug resistance mechanisms that reduce the efficacy of membrane-disrupting antibiotics have evolved in a variety of bacterial pathogens. Similar to mechanisms that thwart antimicrobial agents that target intracellular bacterial elements, resistance to membrane-disrupting agents results from modifications to the target (in this case, lipids), the action of efflux pumps, expression of various drug deactivating agents, and proteolytic degradation. In this review, we describe recent progress in elucidating the various mechanisms of resistance to membrane-disrupting antibiotics.