<p>The emergence of multidrug-resistant bacteria presents a critical threat to global health. These multidrug-resistant bacteria are often protected by complex cell envelopes that many antibiotics cannot penetrate, creating an important barrier to treatment. In response, targeting bacterial envelopes has long been recognized as an effective strategy, offering potential to bypass the challenges of drug entry and efflux resistance mechanisms. Moreover, many unique bacterial envelope sites remain clinically untapped, and new compounds directed at them have the potential to diversify the space of antimicrobial mechanisms, lowering the risk for cross-resistance. Compounds that target non-proteinaceous envelope components, such as lipopolysaccharide or prenylated peptidoglycan-precursors, are particularly attractive owing to their reduced susceptibility to antimicrobial resistance development. In this Review, we explore both recently discovered compounds and established envelope-targeting antibiotics, including compounds that target Gram-positive bacteria, more complex Gram-negative bacteria and mycobacterial pathogens, shedding light on this still clinically underexplored and vital therapeutic approach.</p>