The burden of antibiotic-resistant infections among Gram-negative bacteria is increasing. Resistance to third-generation cephalosporins (3GCs) in Enterobacteriaceae is mainly conferred by the acquisition of β-lactamases or by deregulation of natural genetically-encoded β-lactamase enzymes. Enterobacteriaceae such as Enterobacter spp., Serratia marcescens, Citrobacter freundii, Providencia spp. and Morganella morganii (ESCPM group) possess chromosomally-encoded inducible AmpC β-lactamases. AmpC can be overproduced as a response to β-lactam antibiotic exposure or by constitutive dysfunction of the AmpC regulation system. This overproduction can lead to the inactivation of 3GCs. Based on small clinical studies, international guidelines and expert recommendations suggest that 3GCs should be avoided as definitive therapy for infections caused by ESCPM group organisms. In this narrative review, we discuss the published literature and evaluate the risk related to 3GC use in the case of documented ESCPM infection