Drug fever is a common condition that is frequently misdiagnosed. It is a febrile response that coincides temporally with the administration of a drug and disappears after discontinuation of the offending agent. Drug fever is usually suspected when no other cause for the fever can be elucidated, sometimes after antimicrobial therapy has already been started. In nonsensitized individuals receiving a drug for the first time, the onset of fever is highly variable and differs among drug classes, but most commonly appears after 7–10 days of drug administration and rapidly reverses after discontinuation of the drug. Early diagnosis may reduce inappropriate and potentially harmful and expensive diagnostic and therapeutic interventions. Rechallenge with the offending agent will usually cause recurrence of fever within a few hours, confirming the diagnosis. Rechallenge is controversial and should be performed with extreme caution, since there is a potential for a more severe drug reaction. We describe the mechanisms in the pathophysiology of drug fever and summarize the results of published case reports on the wide variety of agents that are implicated in causing drug fever. Special attention is paid to the role of antimicrobial agents in drug fever.