Reye's syndrome (RS) is an acute, serious, postinfectious, metabolic encephalopathy and fatty infiltration of the liver. Despite prodromes related to viral illnesses, there is no encephalitis or viral invasion, and brain and liver tissue cultures show no viral growth. It typically affects children, but young and rarely older adults may be involved. Classic RS follows influenza B or chickenpox, but many respiratory and other viruses have been implicated. In the 1970s and early 1980s, it was recognized as a prominent cause of mental changes in children, and many infections, drugs, and toxins were suspected in the etiology. An association with the use of salicylates in children with febrile illnesses was recognized. Avoidance of salicylates has been followed by a dramatic decline in cases since the mid-1980s. Because aspirin is still used in combination in over-the-counter cold and other medicines, inadvertent use can occur. Aspirin is widely used in adults, including those with febrile illnesses; it raises at least a theoretical possibility of RS cases in adults. Salicylates most likely exacerbate an underlying disease in susceptible individuals rather than cause it. It is now suspected that at least some of the patients with RS may have had metabolic diseases or toxic exposures that were not recognized in the 1970s and 1980s. These heterogeneous groups of disorders are often labeled as Reyelike syndromes (RLS).