Malaria, a disease with staggering mortality worldwide, is increasingly encountered in US emergency departments. Given both the unfamiliarity of US physicians with the disease and its nonspecific manifestations, the potential for misdiagnosis increases the risk of morbidity and mortality associated with malaria diagnosed in US emergency departments. Maintaining a high index of suspicion and eliciting a travel or blood transfusion history in any patient who presents with fever and nonspecific symptoms is central to making the diagnosis. Spreading resistance to standard antimalarial therapy and the recognition of the mortality associated withPlasmodium falciparuminfection has led to the development of better guidelines for therapy, including intravenous quinidine gluconate therapy and exchange transfusion. This article outlines these and other issues crucial to the diagnosis and management of malaria in the emergency department.