In searching during the early 1950s for new drugs for the treatment of rheumatoid arthritis, little information was available to allow a rational approach. The mode of action of the few drugs available was unknown and even the analgesic action of aspirin could not be demonstrated in animals. A speculative concept was developed that aspirin possessed a specific unidentified action in rheumatoid arthritis and that this and its analgesic properties were related to its ability to delay the development of ultraviolet (UV) erythema in the guinea pig. A series of substituted phenoxypropionic acids proved to be active as antierythemic agents, but the most potent was inactive clinically in rheumatoid arthritis. Refinements to the testing systems led to a series of substituted phenylacetic acids, three of which although active in rheumatoid arthritis produced unacceptable adverse reactions (ADRs). Attempts to relate laboratory data to clinical ADRs suggested that the substituted phenylpropionic acids (originally rejected because of concerns about toxicity) might be better tolerated than we had anticipated. Ibuprofen was selected from this large group. It was proven to be effective and well tolerated and became "the first of the propionics" when it was launched in 1969. In the 1970s, ibuprofen proved to be effective as a prescription drug in a range of painful nonrheumatic conditions and on the basis of its good safety record was approved as an OTC analgesic in 1983 in the United Kingdom and in 1984 in the USA. It has proven to be popular and effective and much safer than aspirin or acetaminophen in overdosage.