ABSTRACTMammalian innate immunity employs several humoral ‘weapons’ that target the bacterial envelope. The threats posed by the multidrug‐resistant ‘ESKAPE’ Gram‐negative pathogens (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are forcing researchers to explore new therapeutic options, including the use of these immune elements. Here we review bacterial envelope‐targeting (peptidoglycan and/or membrane‐targeting) proteins/peptides of the mammalian immune system that are most likely to have therapeutic applications. Firstly we discuss their general features and protective activity against ESKAPE Gram‐negatives in the host. We then gather, integrate, and discuss recent research on experimental therapeutics harnessing their bactericidal power, based on their exogenous administration and also on the discovery of bacterial and/or host targets that improve the performance of this endogenous immunity, as a novel therapeutic concept. We identify weak points and knowledge gaps in current research in this field and suggest areas for future work to obtain successful envelope‐targeting therapeutic options to tackle the challenge of antimicrobial resistance.