Suppression of cell death (most often apoptosis) by survival signals, or by defects in cell death signal transduction pathways, is considered one of the obligate hallmarks of malignant transformation. However, molecular survival strategies to evade cell death only have relevance in the presence of pro-death signals. Discovery of the apoptotic properties of oncogenes responsible for increased tumor cell proliferation (e.g. c-Myc) provided the most important example for such signals and led to the concept of synthetic lethal targeting as a strategy of identifying cancer specific drug target molecules. Besides growth signal autonomy, other hallmarks of oncogenesis (insensitivity to anti-growth signals, limitless replicative potential, invasion and metastasis, angiogenesis and increased genomic instability) are also challenged by increased susceptibility to various forms of cell death. Therefore, cancer cells must acquire survival strategies to suppress these cell death/apoptosis mechanisms. Novel signal transduction therapies can target molecules involved in these strategies to trigger tumor specific cell death.