Folate cofactors are intimately involved in a number of critically important metabolic transformations, including the biosynthesis of purines (ATP, GTP) and pyrimidines (DNA). We discovered a few years ago that 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF, lometrexol) blocks de novo purine biosynthesis; this new compound proved to be a potent inhibitor of cell growth and exhibited excellent therapeutic activity against a broad variety of murine solid tumors and human tumor xenografts. We have more recently prepared a new antifolate that appears to be unique in its ability to inhibit at least five of the essential folate-dependent enzymes in cellular metabolism. This new compound (a pyrrolo[2,3-d]pyrimidine derivative) was licensed to Eli Lilly and became the cancer drug Alimta, now approved worldwide for treatment of both mesothelioma and second-line lung cancer. Multiple clinical trials involving other solid tumors are currently underway. Our current interest is largely focused on the design and synthesis of new inhibitors in an attempt to extend these exciting results, on studies aimed at understanding and further controlling toxicity, and on probing the molecular interactions responsible for the remarkable breadth of inhibitory activity exhibited by this new drug. Our long-standing interest continues in heterocyclic chemistry, and in new synthetic methodology and synthetic applications of molecular rearrangements.