Antibiotic tolerance is the prolonged survival of a bacterial population in the presence of antimicrobials. Tolerance can impact infection outcome and promote the evolution of outright resistance. Opportunistic pathogens, like Enterobacter cloacae, present a danger to immunocompromised individuals and have been identified by the CDC as an urgent threat to human health. Here, using E. cloacae as a model, we study mechanisms of 1) tolerance to cell wall-acting antibiotics and 2) resistance to killing by an antimicrobial peptide (AMP). We observed that E. cloacae displays meropenem (a β-lactam antibiotic) tolerance by forming cell wall-deficient spheroplasts, which resume normal growth after removal of the antibiotic. Presumably, spheroplasts rely on their outer membrane (OM) for structural integrity maintenance. In Chapter 2, we identified the PhoPQ signaling system as a key driver of tolerance. PhoPQ is activated upon exposure to meropenem, promoting OM modifications to enhance OM strength. PhoPQ is essential for optimal meropenem tolerance development, as a deletion mutant exhibits drastically reduced survival in the presence of drug. Further, we identified an inhibitor of PhoPQ which significantly reduces E. cloacae tolerance to meropenem. Interestingly, the OM modifications that promote tolerance are the same that promote resistance against antimicrobial peptides (AMPs). These short, naturally occurring peptides display potent antimicrobial activity across a wide range of pathogens, often through interactions with bacterial membranes. It is vital to understand mechanisms by which bacteria resist the effects of AMPs as they may become a viable infection treatment strategy. In Chapter 3, we investigated E. cloacae resistance mechanisms against cecropin, an insect AMP of therapeutic interest. E. cloacae cecropin resistance is heterogeneous within a population and highly dependent on initial cell density. Surviving cells are susceptible to subsequent doses of cecropin, suggesting unstable, stochastic resistance (i.e., heteroresistance). Heteroresistance collectively relies on outer membrane modifications, potential capsule production, and membrane-bound protease activity.This work reveals mechanisms by which an opportunistic pathogen survives treatment with cell-envelope targeting antimicrobials. These insights lay the groundwork for the development of novel treatment strategies to combat the looming threat of multidrug resistant infections.