The interrelated enzymic reactions of folate metabolism are presented and key tetrahydrofolate-producing reactions are emphasized. As observed with the methotrexate (MTX)-resistant mutant strain Streptococcus faecium var. durans/Ak, the regulatory roles of serine and purines in controlling their own synthesis by the repression of enzymes required for co-factor synthesis are reviewed. Positive induction of the dihydrofolate reductase activity of this mutant by folate and the antagonism of the folate effect by purines and thymine are discussed. A protective agent of the reductase-active protein, MTX is viewed also as a "positive" inducer of dihydrofolate reductase. Preliminary studies with L1210 leukemia-bearing mice and the murine leukemia ERLD in vitro suggest that citrovorum factor (CF) also triggers a positive induction of the reductase of the small intestine and of ERLD cells without apparently influencing the reductase level of L1210 in vivo. The possibility that control mechanisms, by which MTX and CF indirectly regulate enzyme synthesis in drug-stressed, CF-rescued cells, contribute to the success of high-dose MTX-CF rescue therapy is introduced.