Multidrug-resistant Gram-negative bacteria pose a serious and rapidly emerging threat to patients in healthcare settings and are especially prevalent and problematic in intensive care units. Few antimicrobial treatment options remain for patients infected with the most resistant of these pathogens. Recent data shed light on the extent of the multidrug-resistant Gram-negative problem and suggest potential strategies to prevent transmission and improve clinical outcomes. This review examines the clinical impact and epidemiology of multidrug-resistant Gram-negative bacteria as a cause of healthcare-associated infections in critically ill patients, discusses issues regarding detection and recognition of these organisms, and reviews recommended methods to prevent patient-to-patient transmission of these formidable pathogens. Recent guidance from the Centers for Disease Control and Prevention for detection and control of carbapenemase-producing Enterobacteriaceae is discussed, along with potential strategies to optimize the existing antimicrobial treatment options for patients with multidrug-resistant Gram-negative infections.