Sixty years ago, 6‐thioguanine (6‐TG) was introduced into the clinic. We suggest its full potential in therapy may not have been reached. In this paper, we contrast 6‐TG and the more widely used 6‐mercaptopurine; discuss 6‐TG metabolism, pharmacokinetics, dosage and schedule; and summarize many of the early studies that have shown infrequent but nevertheless positive results with 6‐TG treatment of cancers. We also consider studies that suggest that combinations of 6‐TG with other agents may enhance antitumor effects. Although not yet tested in man, 6‐TG has recently been proposed to treat a wide variety of cancers with a high frequency of homozygous deletion of the gene for methylthioadenosine phosphorylase (MTAP), often codeleted with the adjacent tumor suppressor CDKN2A (p16). Among the cancers with a high frequency of MTAP deficiency are leukemias, lymphomas, mesothelioma, melanoma, biliary tract cancer, glioblastoma, osteosarcoma, soft tissue sarcoma, neuroendocrine tumors, and lung, pancreatic, and squamous cell carcinomas. The method involves pretreatment with the naturally occurring nucleoside methylthioadenosine (MTA), the substrate for the enzyme MTAP. MTA pretreatment protects normal host tissues, but not MTAP‐deficient cancers, from 6‐TG toxicity and permits administration of doses of 6‐TG that are much higher than can now be safely administered. The combination of MTA/6‐TG has produced substantial shrinkage or slowing of growth in two different xenograft human tumor models: lymphoblastic leukemia and metastatic prostate carcinoma with neuroendocrine features. Further development and a clinical trial of the proposed MTA/6‐TG treatment of MTAP‐deficient cancers seem warranted. This review suggests that the full potential of 6‐thioguanine (6‐TG) in cancer therapy may not have been reached. The authors contrast 6‐TG and the more widely used 6‐mercaptopurine; discuss 6‐TG metabolism, pharmacokinetics, dosage and schedule; and summarize many of the early studies that have shown infrequent but nevertheless positive results with 6‐TG treatment. The combination of 6‐TG and a natural compound, methylthioadenosine (MTA), may provide selective treatment of cancers that have lost the gene methylthioadenosine phosphorylase (MTAP). Administration of MTA decreases 6‐TG toxicity to normal host tissues, thus permitting use of increased therapeutic doses of 6‐TG. Combinations of 6‐TG with other agents, such as methotrexate or pralatrexate, may also enhance therapeutic effects in MTAP‐deficient tumors.