Cancer cells contain multiple signal transduction pathways whose activities are frequently elevated due to their transformation, and that are often activated following exposure to established cytotoxic therapies including ionizing radiation and chemical DNA damaging agents. Many pathways activated in response to transformation or toxic stresses promote cell growth and invasion and counteract the processes of cell death. As a result of these findings many drugs, predominantly protein and lipid kinase inhibitors, of varying specificities, have been developed to block signaling by cell survival pathways in the hope of killing tumor cells and sensitizing them to toxic therapies. Unfortunately, due to the plasticity of signaling processes within a tumor cell, inhibition of any one growth factor receptor or signaling pathway frequently has only modest long-term effects on cancer cell viability, tumor growth, and patient survival. As a result of this realization, a greater emphasis has begun to be placed on rational combinations of drugs that simultaneously inhibit multiple inter-linked signal transduction/survival pathways. This, it is hoped, will limit the ability of tumor cells to adapt and survive because the activity within multiple parallel survival signaling pathways has been reduced. This review will discuss some of the approaches that have been taken to combine signal transduction modulatory agents to achieve enhanced tumor cell killing.