The history of regulatory mass spectrometry at the Food and Drug Administration began in the early 1960s and was initiated by J. N. Damico using a time-of-flight instrument with limited mass range, resolution and sensitivity. Early work involved confirmation of identity of compounds using direct probe introduction and full mass scans. From 1964 to 1969 an important application of mass spectrometry was the analysis of pesticides and elucidation of their fragmentation pathways. Regulatory mass spectrometry was used to confirm manually trapped gas chromatographic peaks, and it solved the problem of false positive identifications based solely on gas chromatographic retention time. In time the mass spectrometer became viewed as the ultimate gas chromatographic detector. Another important early regulatory case involved the question of Krebiozen as a cancer cure. Krebiozen was analyzed by mass spectrometry and found to consist of creatinine, which was known to have no activity as an anti-cancer drug. Such basic information as the identity of a substance demonstrated the indispensable regulatory use of mass spectrometry. The basic problem of identification has broadened in scope to include multicomponent analyses, trace level detection, quantitation, and newer ionization techniques. Two examples illustrate the continuing development of regulatory mass spectrometry, Negative ion chemical ionization mass spectrometry in the analysis of aflatoxin B1 involves use of a newer ionization technique. The requirements of trace level detection and specificity are further stretched in the gas chromatographic mass spectrometric selected ion monitoring detection, confirmation and quantitation of tetrachlorodibenzo-p-dioxins.