Publisher Summary This chapter focuses on antagonists of purine and pyrimidine metabolites and of folic acid. The range of antifolic acids, antipurines, and antipyrimidines dealt with has been confined to those that inhibit experimental tumors. An interesting relationship between the action of hormones and of antipurines and antifolic acids has been discussed in the chapter. Antipyrimidines discussed in the chapter include 5-Fluorouracil, 5-Iodo- and 5-Bromo- derivatives of uracil, Chlorouracil, Uracil-6-Methyl-Sulfone, 6-Azauracil, urethane, and other pyrimidine analogs . Antipurines are structural analogs of purine derivatives used in normal metabolism, and are thus able to interfere with growth. The essential role of Methotrexate and similar antagonists is to prevent the reduction of folic acid to tetrahydrofolic acid, which can then be readily formylated to folinic acid or “activated formate,” or combined with a “one carbon” unit at a lower stage of oxidation. The increased folinic acid excretion is a measure of an increased conversion of folic to folinic acid, which is essentially required in the synthesis of nucleic acid. The chapter closes with a discussion on conceivable relation among the mechanisms of action of biological alkylating agents and purine antimetabolites.