John Walshe first described the use of penicillamine in Wilsons disease in 1956. He had discovered the compound in the urine of patients (including himself) who had taken penicillin, and experimentally confirmed that it increased urinary copper excretion by chelation. He had initial difficulty convincing several world experts of the time (Denny Brown and Cumings) of its efficacy, as they held that Wilsons disease was not primarily a problem of copper homeostasis but of amino acid metabolism, and that dimercaprol should be used as a chelator. Later studies confirmed both the copper-centered theory and the efficacy of -penicillamine. Walshe also pioneered other chelators in Wilson's such as triethylene tetramine and tetrathiomolybdate.
Penicillamine was first synthesized by John Cornforth under supervision of Robert Robinson.
Penicillamine has been used in rheumatoid arthritis since the first successful case in 1964.