Over the past decade progress has been made in the development of therapies against cancer. Small molecules, mainly tyrosine kinase inhibitors (tyrphostins) like Gleevec, Iressa targeting CML and EGFR overexpressing tumors have entered the clinic, where a large number of other tyrphostins are at various stages of clinical development. In parallel a few antibodies like Herceptin targeting breast cancer overexpressing Her-2 and Rituxan targeting B cell malignancies are utilized in the clinic. In all these cases success is moderate and restricted to a narrow population of patients, except for Gleevec which is effective for a long duration for chronic CML. The cancer community agrees that this is actually a unique exception that proves the rule. Over the past few years a few modalities of cancer gene therapies have emerged. In this short review we shall summarize our efforts to develop methods to activate PKR selectively in cancer cells.