Carbapenem-resistant Enterobacteriaceae (CRE) are a major public health threat, causing significant morbidity and mortality. These bacteria develop resistance through mechanisms such as β-lactamase production and carbapenemase activity, which are often carried on mobile genetic elements. The global spread of carbapenemase-producing Enterobacteriaceae (CPE) has accelerated in recent decades, with Klebsiella pneumoniae carbapenemase (KPC) being a key transmissible gene. KPC-producing strains are associated with high resistance to multiple antibiotics, leading to multidrug-resistant organisms (MDROs). The spread of KPC is linked to clonal expansion of K. pneumoniae strains, particularly those of clonal complex 258 (CC258), and is often found in hospitals. Other carbapenemases, such as OXA-48 and NDM-1, are also prevalent, with OXA-48 found in the Indian subcontinent and NDM-1 in various regions, including Greece and South America. The spread of these enzymes is facilitated by plasmids and mobile genetic elements, and their presence in the environment, such as in water, poses additional risks. In the United States, KPC-producing bacteria have become endemic in several states, with high prevalence in hospitals. CRE infections are associated with high mortality rates, and the spread of these pathogens is a growing concern. Control measures include infection control practices, surveillance, and education. The clinical epidemiology of KPC-producing Enterobacteriaceae in the U.S. shows that these bacteria are primarily a problem in inpatient settings, with risk factors including critical illness, prolonged hospitalization, and use of invasive devices. In children, CRE prevalence has increased, though data are limited. The global distribution of CRE is widespread, with high prevalence in regions such as Greece, Israel, and Latin America. The emergence of new resistance mechanisms, such as plasmid-mediated polymyxin resistance (mcr-1), poses additional threats. Overall, the evolution of CRE and the spread of carbapenemases represent a significant challenge to global public health, requiring coordinated efforts in surveillance, infection control, and antimicrobial stewardship to mitigate their impact.Carbapenem-resistant Enterobacteriaceae (CRE) are a major public health threat, causing significant morbidity and mortality. These bacteria develop resistance through mechanisms such as β-lactamase production and carbapenemase activity, which are often carried on mobile genetic elements. The global spread of carbapenemase-producing Enterobacteriaceae (CPE) has accelerated in recent decades, with Klebsiella pneumoniae carbapenemase (KPC) being a key transmissible gene. KPC-producing strains are associated with high resistance to multiple antibiotics, leading to multidrug-resistant organisms (MDROs). The spread of KPC is linked to clonal expansion of K. pneumoniae strains, particularly those of clonal complex 258 (CC258), and is often found in hospitals. Other carbapenemases, such as OXA-48 and NDM-1, are also prevalent, with OXA-48 found in the Indian subcontinent and NDM-1 in various regions, including Greece and South America. The spread of these enzymes is facilitated by plasmids and mobile genetic elements, and their presence in the environment, such as in water, poses additional risks. In the United States, KPC-producing bacteria have become endemic in several states, with high prevalence in hospitals. CRE infections are associated with high mortality rates, and the spread of these pathogens is a growing concern. Control measures include infection control practices, surveillance, and education. The clinical epidemiology of KPC-producing Enterobacteriaceae in the U.S. shows that these bacteria are primarily a problem in inpatient settings, with risk factors including critical illness, prolonged hospitalization, and use of invasive devices. In children, CRE prevalence has increased, though data are limited. The global distribution of CRE is widespread, with high prevalence in regions such as Greece, Israel, and Latin America. The emergence of new resistance mechanisms, such as plasmid-mediated polymyxin resistance (mcr-1), poses additional threats. Overall, the evolution of CRE and the spread of carbapenemases represent a significant challenge to global public health, requiring coordinated efforts in surveillance, infection control, and antimicrobial stewardship to mitigate their impact.