Acute lymphoblastic leukemia (ALL) is the most common form of leukemia in children. Though current therapies assure that virtually 100% of both B- and T-cell ALL (T-ALL) will achieve a successful induction of remission, within 5 years approximately 20% will relapse of the disease and go on to die of intractable leukemia. In light of advancing genomic knowledge, new paradigms have emerged that might explain some of our successes and may help conquer some of our failures. ALL arises from precursors of B cells and less commonly from precursors of T-cells. T-cell leukemia is more difficult to treat and is frequently characterized by chromosomal abnormalities of 9p21. Localized to this region are the cell cycle regulatory genes p16 (CDKN2A, INK4A), p15 (CDKN2B, INK4B) and ARF. This region also harbors the methylthioadenosine phosphorylase (MTAP) gene, which is involved in purine salvage. Each of these genes are frequently inactivated in T-ALL and a wide variety of other cancers. The loss of p16 function removes a constitutive “brake” on cell replication and allows activated oncogenes to stimulate runaway malignant proliferation. The loss of MTAP in the replicating malignant cells limits purine salvage, shifting the burden for purine synthesis to the more resource intensive de novo pathway. As the role of p16 is cyclin dependent kinase (CDK) inhibition, small molecule inhibitors of the CDKs that substitute for the action of p16 are in development as therapeutic agents. With regard to MTAP, cells lacking this enzyme are uniquely susceptible to inhibitors of de novo purine synthesis. Inactivation of these genes also occurs in a variety of other cancers. In this review, we will explore the current knowledge of the status of these genes in T-ALL, their roles in disease etiology and outcome, and how these abnormalities can provide selective molecular targets for cancer therapy.