Signal transduction therapy for cancer targets pathways that are over-active in cancer cells and upon which the cancer cells depend for their survival. Protein kinases are prime targets for signal transduction therapy. A major breakthrough was the introduction of the Bcr-Abl inhibitor imatinib/Gleevec into the clinic for the treatment of chronic myelogenous leukemia (CML). Nevertheless, even for this clonal disease, which has a well-characterized principle survival factor, signal transduction therapy faces two major problems: the emergence of drug-resistant clones and the persistence of a small population of cancer stem cells that re-establish the leukemia if treatment is stopped. Most cancers are far more heterogeneous than CML, so choosing the appropriate molecular targets is a major challenge. Signal transduction therapy can potentially reduce tumor mass and control cancer as a chronic disease. Complete cures will require ways of combating cancer stem cells and preventing metastasis, such as harnessing bystander effects and the immune system during treatment.