West Nile virus (WNV) infection recently became a major public health concern in the western hemisphere. This article describes recent information regarding previously unrecognized mechanisms of WNV transmission and reviews clinical manifestations of WNV infection, diagnostic tests, and prevention strategies from a pediatric perspective. WNV is transmitted to humans primarily through the bite of infected mosquitoes, but during the epidemic that spread across North America in 2002, transmission of WNV through blood transfusions and organ transplantation was described for the first time. Individual case reports indicate that WNV can be transmitted also in utero and probably through breast milk. Although most WNV infections are asymptomatic, the virus causes a broad range of manifestations from uncomplicated febrile illness to meningitis, neuropathies, paralysis, and encephalitis. Severe manifestations of WNV infection are far more common in adults than in children, but 105 cases of neuroinvasive WNV disease were reported among children in the United States in 2002. The distribution of the virus in North America continues to spread. WNV infection can be diagnosed by detecting WNV-specific antibody in cerebrospinal fluid or serum, or by detecting the virus or viral nucleic acid in cerebrospinal fluid, blood, or tissues. Cornerstones of prevention include personal protection against mosquitoes, including wearing insect repellent, reducing populations of vector mosquitoes, and screening the blood supply for WNV-contaminated blood donations.