This review summarizes the major advances that had been reported since the outstanding contributions that Professor Benet and his group had made in the 1980’s and 1990’s concerning the metabolism and pharmacologic action of organic nitrates (ORN). Several pivotal studies have now enhanced our understanding of the metabolism and the bioactivation of ORN, resulting in the identification of a host of cysteine-containing enzymes that can carry out this function. Three isoforms of aldehyde dehydrogenase, all of which with active catalytic cysteine sites, are now known to metabolize, somewhat selectively, various members of the ORN family. The existence of a long-proposed but unstable thionitrate intermediate from organic nitrate metabolism has now been experimentally observed. ORN-induced thiol oxidation in multiple proteins, called the “Thionitrate Oxidation Hypothesis”, can be used not only to explain the phenomenon of nitrate tolerance, but also the various consequences of chronic nitrate therapy, viz., rebound vasoconstriction, and increased morbidity and mortality. Thus, a unifying biochemical hypothesis can account for the myriad of pharmacological events resulting from nitrate therapy. Optimization of future uses of ORN in cardiology and other diseases could benefit from further elaboration of this unifying hypothesis.