Antimicrobial resistance (AMR) has emerged as one of the most pressing global health challenges of the 21st century, currently responsible for approximately 700,000 deaths annually and projected to cause up to 10 million deaths per year by 2050 if left unchecked. The rapid rise of multidrug-resistant (MDR) pathogens, combined with a stagnating antibiotic discovery pipeline, has severely limited effective treatment options. This challenge is further compounded by complex infection phenotypes such as biofilms, persister cells, and intracellular pathogens, which significantly reduce therapeutic efficacy and contribute to chronic and recurrent infections. A central challenge in combating AMR is the development of strategies that can overcome resistance mechanisms while maintaining selectivity and minimizing host toxicity. In this context, the bacterial cell envelope represents a highly attractive “Achilles’ heel,” given its essential role in maintaining cellular integrity and its fundamental differences from mammalian cell membranes. In this talk, I will present our group’s efforts toward developing cell-envelope-targeted therapeutic strategies to address AMR. We have engineered multifunctional semisynthetic glycopeptide antibiotics designed to target multiple components of the bacterial cell envelope, thereby enabling potent activity against resistant pathogens and complex infection states. In parallel, inspired by antimicrobial peptides and lipopeptides, we have developed a diverse class of peptidomimetics that integrate cationic and hydrophobic features to selectively disrupt bacterial membranes. These molecules exhibit metabolism-independent bactericidal activity, allowing efficient eradication of MDR bacteria, including biofilms, persisters, and intracellular pathogens. Furthermore, we have developed weak membrane-perturbing antibiotic adjuvants that enhance the efficacy of existing antibiotics by improving membrane permeability and overcoming intrinsic resistance mechanisms. This approach offers a practical and scalable strategy to revive obsolete antibiotics and extend their clinical lifespan.