Dihydrofolate reductase (DHFR) is a member of the reductase family of enzymes that is ubiquitously expressed in all organisms. DHFR catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, and it is essential for the synthesis of thymidylate, purines and several amino acids. Expression of methotrexate (MTX)-resistant variants of DHFR in normal hematopoietic cells is a potential strategy to permit administration of larger doses of MTX by alleviating drug toxicity in normal cells and tissues that are drug sensitive.