Aerobic gram-negative bacilli, including the family of Enterobacteriaceae and non-lactose fermenting bacteria such as Pseudomonas and Acinetobacter species, are major causes of hospital-acquired infections. The rate of antibiotic resistance among these pathogens has accelerated dramatically in recent years and has reached pandemic scale. It is no longer uncommon to encounter gram-negative infections that are untreatable using conventional antibiotics in hospitalized patients. In this review, we provide a summary of the major classes of gram-negative bacilli and their key mechanisms of antimicrobial resistance, discuss approaches to the treatment of these difficult infections, and outline methods to slow the further spread of resistance mechanisms.