Childhood fever of unknown origin (FUO) is most often related to an underlying infection but can also be associated with a variety of neoplastic, rheumatologic, and inflammatory conditions. Repeated, focused reviews of patient history and physical examination are often helpful in suggesting a likely diagnosis. Diagnostic workup should be staged, usually leaving invasive testing for last. Advances in molecular genetic techniques have increased the importance of these assays in the diagnosis of FUO in children.