Infection prevention remains a major challenge in emergency care. Acutely ill and injured patients seeking evaluation and treatment in the emergency department (ED) not only have the potential to spread communicable infectious diseases to health care personnel and other patients, but are vulnerable to acquiring new infections associated with the care they receive. This article will evaluate these risks and review the existing literature for infection prevention practices in the ED, ranging from hand hygiene, standard and transmission-based precautions, health care personnel vaccination, and environmental controls to strategies for preventing health care-associated infections. We will conclude by examining what can be done to optimize infection prevention in the ED and identify gaps in knowledge where further research is needed. Successful implementation of evidence-based practices coupled with innovation of novel approaches and technologies tailored specifically to the complex and dynamic environment of the ED are the keys to raising the standard for infection prevention and patient safety in emergency care.