Overutilization of antibiotics and emergence of resistant bacteria are important problems, particularly in intensive care units. To date, reproducible interventions to improve antibiotic utilization in hospitals have not been proven to be effective or safe. Evidence-based medicine, clinical practice guidelines, and health information technology are frequently promoted as means to cross the “quality chasm” described by the Institute of Medicine. This article outlines how these approaches intersect in a strategy for quality improvement research evaluating the safety and effectiveness of clinical practice guidelines designed to improve antibiotic use in neonatal intensive care units. Considerable evidence suggests that antibiotic overuse selects for bacterial resistance (1), and several investigators have shown a close association between antibiotic use and the emergence of antibiotic-resistant bacteria (2-7). To address the growing problem of antibiotic resistance, the Centers for Disease Control and Prevention, the National Foundation for Infectious Diseases, the Society for Healthcare Epidemiology of America, and the Infectious Disease Society of America have all urged hospitals to develop systems to monitor antibiotic use and urged physicians to reduce inappropriate antibiotic use (8-10). Antibiotic stewardship is increasingly the subject of research, discussion, and debate (11).