Over the past 30 years, significant advances have transformed the landscape of human immunodeficiency virus (HIV) care in the emergency department. Diagnosis and management of HIV has improved, resulting in a decline in the incidence of acquired immunodeficiency syndrome (AIDS)-defining infections. Advances in pharmacology have led to fewer serious medication toxicities and more tolerable regimens. Emergency providers have played an increasingly important role in HIV screening and diagnosis of acute infection. Provision of postexposure prophylaxis is expanding from a focus on occupational exposure to include all high-risk cases.