Although largely investigated in adults, the issue of hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) in childhood is unsettled due to lack of sufficient data. The purpose of this study is to examine the clinical syndromes of hypersensitivity to NSAIDs in children and adolescents. We performed a review of relevant papers on cutaneous and respiratory adverse reactions triggered by NSAIDs in pediatric patients, and a recount of our own experience in 43 well-characterized NSAID-sensitive children with cutaneous reactions who were submitted to controlled oral challenges with NSAIDs and the new inhibitors of the enzyme isoform cyclooxygenase-2 (COX-2). Although it has been suggested that allergic and pseudoallergic reactions to NSAIDs in children occur rarely, their prevalence remains largely unknown due to the scarcity of studies. About 23% of NSAID-sensitive patients seen in our institutions are young patients aged 8–18 yr who more frequently develop facial angioedema as their main clinical manifestation. Most patients are atopic and show reactions to more than one drug (cross-reactors). Drugs that inhibit COX-2 with higher specificity than classic NSAIDs are better tolerated in young NSAID-hypersensitive patients.