Carbapenem-resistant Enterobacteriaceae (CRE) pose a significant public health threat due to their high morbidity and mortality rates. The rapid spread of antibiotic-resistant gram-negative bacteria (GNB) is driven by the presence of β-lactamase genes carried on mobile genetic elements. Transmissible carbapenem-resistance in Enterobacteriaceae has been recognized for two decades, but the global dissemination of carbapenemase-producing Enterobacteriaceae (CPE) is a more recent and alarming problem. This article discusses the evolution of CRE, focusing on the epidemiology of the CPE pandemic, risk factors for colonization and infection with *Klebsiella pneumoniae* carbapenemase–producing *K. pneumoniae*, and strategies to halt the spread of these pathogens. The most common transmissible CPE worldwide is *K. pneumoniae* carbapenemase–producing *K. pneumoniae*, which is associated with clonal complex 258 (CC258) and multilocus sequence type (ST) 258 strains. Other notable carbapenemases include class D OXA β-lactamases, particularly OXA-48, and class B metallo-β-lactamases (MBLs), such as IMP, VIM, and NDM. The global distribution of these carbapenemases is highlighted, with regions like Greece, Israel, Latin America, and the United States experiencing high prevalence rates. Interventions to control the spread of CRE in healthcare settings include bundled infection control measures, patient cohorts, contact isolation, dedicated staffs, daily bathing with chlorhexidine, improved hand hygiene, and environmental cleaning. The emergence of plasmid-mediated colistin resistance, associated with the mcr-1 gene, represents a new public health threat. Early recognition and timely prevention strategies are crucial to combat the evolving threat of CRE.Carbapenem-resistant Enterobacteriaceae (CRE) pose a significant public health threat due to their high morbidity and mortality rates. The rapid spread of antibiotic-resistant gram-negative bacteria (GNB) is driven by the presence of β-lactamase genes carried on mobile genetic elements. Transmissible carbapenem-resistance in Enterobacteriaceae has been recognized for two decades, but the global dissemination of carbapenemase-producing Enterobacteriaceae (CPE) is a more recent and alarming problem. This article discusses the evolution of CRE, focusing on the epidemiology of the CPE pandemic, risk factors for colonization and infection with *Klebsiella pneumoniae* carbapenemase–producing *K. pneumoniae*, and strategies to halt the spread of these pathogens. The most common transmissible CPE worldwide is *K. pneumoniae* carbapenemase–producing *K. pneumoniae*, which is associated with clonal complex 258 (CC258) and multilocus sequence type (ST) 258 strains. Other notable carbapenemases include class D OXA β-lactamases, particularly OXA-48, and class B metallo-β-lactamases (MBLs), such as IMP, VIM, and NDM. The global distribution of these carbapenemases is highlighted, with regions like Greece, Israel, Latin America, and the United States experiencing high prevalence rates. Interventions to control the spread of CRE in healthcare settings include bundled infection control measures, patient cohorts, contact isolation, dedicated staffs, daily bathing with chlorhexidine, improved hand hygiene, and environmental cleaning. The emergence of plasmid-mediated colistin resistance, associated with the mcr-1 gene, represents a new public health threat. Early recognition and timely prevention strategies are crucial to combat the evolving threat of CRE.