Any patient presenting to the emergency department (ED) with fever triggers consideration of the administration of an antimicrobial. Empiric antimicrobial therapy has become a cornerstone of treatment. Frequently, the decision to initiate empiric treatment needs to be made before the definitive diagnosis is known. In such cases, an organized approach is helpful. This article aims to provide a systems-based approach to prescribing antimicrobials to patients presenting to the ED with fever, while understanding the risk associated with overutilization. An understanding of the key considerations is needed to ensure that decisions are made well and appropriate treatment begins promptly.