Carbapenem-Resistant Enterobacteriaceae (CRE) have become a significant public health concern in the United States due to their resistance to broad-spectrum antibiotics and high mortality rates. Over the past decade, the spread of Klebsiella pneumoniae carbapenemase (KPC) has increased the prevalence of CRE. Other carbapenemase subtypes, such as New Delhi metallo-β-lactamase (NDM), have also been identified, and these enzymes are often found on mobile genetic elements, facilitating their spread. CRE are particularly problematic because they cause frequent infections, are associated with high mortality, and can spread widely. CRE have primarily been recognized in healthcare settings, but Enterobacteriaceae are common causes of both healthcare and community infections, raising the possibility of CRE spreading into the community. The limited treatment options for CRE infections have made them of national epidemiologic importance. This review describes the current epidemiology of CRE in the United States and highlights important prevention strategies. Before 1992, CRE were uncommon in the United States. However, over the last decade, CRE have been reported more frequently. The emergence of carbapenemases, such as KPC, has contributed to the increased prevalence of CRE. KPC is the most common carbapenemase in the United States and is associated with the spread of CRE. KPC-producing isolates have become more widespread nationally, and reports of KPC-producing Enterobacteriaceae have emerged from other parts of the world, suggesting intercontinental spread. In the United States, much of the dissemination of KPC-producing CRE isolates appears to be clonal. A sample of KPC-producing K. pneumoniae isolates sent to the CDC from 1996 to 2008 was characterized using PFGE and MLST, revealing that a dominant strain, ST258, accounted for approximately 70% of all KPC-producing K. pneumoniae isolates sent to the CDC during that time period. KPC-producing isolates demonstrate resistance to many agents commonly used to treat gram-negative bacteria, including quinolones and aminoglycosides. Among 344 isolates of KPC-producing Enterobacteriaceae sent to the CDC for evaluation, 91% had a colistin MIC ≤ 2 μg/mL, and 88% had a tigecycline MIC ≤ 2 μg/mL. Only 2 isolates were nonsusceptible to both colistin and tigecycline. The Ambler class B metallo-β-lactamases (MBLs) differ from other carbapenemases by the utilization of zinc at the active site. Although MBLs have been described in Pseudomonas species, they have only rarely been reported among EnterobacteriaceaeCarbapenem-Resistant Enterobacteriaceae (CRE) have become a significant public health concern in the United States due to their resistance to broad-spectrum antibiotics and high mortality rates. Over the past decade, the spread of Klebsiella pneumoniae carbapenemase (KPC) has increased the prevalence of CRE. Other carbapenemase subtypes, such as New Delhi metallo-β-lactamase (NDM), have also been identified, and these enzymes are often found on mobile genetic elements, facilitating their spread. CRE are particularly problematic because they cause frequent infections, are associated with high mortality, and can spread widely. CRE have primarily been recognized in healthcare settings, but Enterobacteriaceae are common causes of both healthcare and community infections, raising the possibility of CRE spreading into the community. The limited treatment options for CRE infections have made them of national epidemiologic importance. This review describes the current epidemiology of CRE in the United States and highlights important prevention strategies. Before 1992, CRE were uncommon in the United States. However, over the last decade, CRE have been reported more frequently. The emergence of carbapenemases, such as KPC, has contributed to the increased prevalence of CRE. KPC is the most common carbapenemase in the United States and is associated with the spread of CRE. KPC-producing isolates have become more widespread nationally, and reports of KPC-producing Enterobacteriaceae have emerged from other parts of the world, suggesting intercontinental spread. In the United States, much of the dissemination of KPC-producing CRE isolates appears to be clonal. A sample of KPC-producing K. pneumoniae isolates sent to the CDC from 1996 to 2008 was characterized using PFGE and MLST, revealing that a dominant strain, ST258, accounted for approximately 70% of all KPC-producing K. pneumoniae isolates sent to the CDC during that time period. KPC-producing isolates demonstrate resistance to many agents commonly used to treat gram-negative bacteria, including quinolones and aminoglycosides. Among 344 isolates of KPC-producing Enterobacteriaceae sent to the CDC for evaluation, 91% had a colistin MIC ≤ 2 μg/mL, and 88% had a tigecycline MIC ≤ 2 μg/mL. Only 2 isolates were nonsusceptible to both colistin and tigecycline. The Ambler class B metallo-β-lactamases (MBLs) differ from other carbapenemases by the utilization of zinc at the active site. Although MBLs have been described in Pseudomonas species, they have only rarely been reported among Enterobacteriaceae