Bacteria within the family Enterobacteriaceae are important pathogens in nosocomial and community settings. Over the past two decades, antimicrobial resistance among Enterobacteriaceae dramatically escalated worldwide. The authors review the mechanisms of antimicrobial resistance among Enterobacteriaceae, epidemiology and global spread of resistance elements and discuss therapeutic options. An exhaustive search for literature relating to Enterobacteriaceae was performed using PubMed, using the following key words: Enterobacteriaceae; Klebsiella pneumoniae; Escherichia coli; antimicrobial resistance; plasmids; global epidemiology; carbapenemases (CPEs); extended spectrum β-lactamases (ESBLs) and multidrug resistance (MDR). Enterobacteriaceae are inhabitants of intestinal flora and spread easily among humans (via hand carriage, contaminated food or water or environmental sources). Antimicrobial resistance may develop via plasmids, transposons or other mobile resistance elements. Mutations conferring resistance typically increase over time; the rate of increase is amplified by selection pressure from antibiotic use. Factors that enhance spread of antimicrobial resistance include: crowding; lack of hygiene; overuse and over-the-counter use of antibiotics; tourism; refugees and international travel. Clonal spread of resistant organisms among hospitals, geographic regions and continents has globally fueled the explosive rise in resistance. The emergence and widespread dissemination of MDR clones containing novel resistance elements (particularly ESBLs and CPEs) has greatly limited therapeutic options. In some cases, infections due to MDR Enterobacteriaceae are untreatable with existing antimicrobial agents. The authors discuss current and future therapeutic options for difficult-to-treat infections due to these organisms.