The first modern description of respiratory syndrome of aspirin hypersensitivity was published over half of the century ago, but the pathogenesis of the disease is still elusive. Just a few years after discovery how aspirin works, Andrew Szczeklik and his co-workers described that asthmatics with aspirin hypersensitivity cross-react to the whole class of nonsteroidal anti-inflammatory drugs. It took rest of his life to seek for an answer on how this disease, nowadays referred to as N-ERD, develops and how it can be treated. In the meantime, cysteinyl leukotrienes, leukotriene modifying drugs, and novel subpopulations of lymphocytes were discovered. This review on aspirin hypersensitivity documents a progress in our understanding of mechanisms of hypersensitivity to nonsteroidal anti-inflammatory drugs. Current concepts about origin of the disease integrate advances in the field of allergology and inflammatory mechanisms of asthma. However, pharmacological inhibition of prostaglandin biosynthesis by nonsteroidal anti-inflammatory drugs has a pivotal role in these investigations. Presented is a central role of prostaglandin E2, a double-faced lipid immunoregulatory mediator whose deficiency is related to the administration of an anti-inflammatory drug. Discussed are cysteinyl leukotrienes, the most reliable biomarkers of aspirin hypersensitivity and cells of innate immunity capable of leukotrienes production. Involvement of blood platelets and recently described mucosal basophils are areas of ongoing studies in the disease. Aspirin hypersensitivity is an acquired condition; therefore, the search for genetic predisposition using classic association studies was inconclusive. There is a new hope to explain mechanisms of aspirin hypersensitivity by studies of innate lymphoid cells, which have a central role in the regulation of respiratory mucosa function in asthma.