Healthcare-associated infections (HAIs) cause significant morbidity and mortality. Recognition of the burden, cost, and preventability of HAIs has resulted in new initiatives to encourage adherence to recommended infection prevention practices and new research to better understand the pathogenesis of HAIs and to develop novel approaches to prevention. Although substantial progress in HAI prevention has been made over the past decade, many opportunities for improvement remain and new challenges continue to arise. Optimal protection of patients from the harms associated with HAIs will require not only allocation of adequate financial resources and additional scientific research, but also a strong commitment to excellence among all healthcare providers, including consistent use of proven prevention practices and appropriate use of antimicrobial agents. Although it is a daunting task, there has never been a better opportunity for the healthcare system to make the changes necessary to achieve the goal of elimination of HAIs.