Regulation of cell death (apoptosis) is frequently affected in the development of malignant diseases, and all molecular steps from extracellular signalling receptors through intracellular pathways, cell death rheostats and cell death executioners may be involved. Bcl-2 is an anti-apoptotic member of a family of anti- and pro-apoptotic proteins that is upregulated in a variety of cancers and specifically overexpressed through chromosomal translocation in some non-Hodgkin lymphomas. Experimental attenuation of Bcl-2 lowers the threshold for undergoing chemotherapy-induced apoptosis. Therefore, therapeutic targeting of Bcl-2 appears as an attractive approach currently intensely explored using mRNA degradation strategies and small inhibitory molecules. One phosphorothioate oligodeoxynucleotide antisense against Bcl-2 mRNA, oblimersen (Genasense™, G3139), has been used in a substantial number of clinical trials. In this review we will discuss the current developments of G3139, and scrutinize its proposed mechanism of action. Several studies indicate that G3139 involves various intracellular mechanisms and modulation of the immune system. To this date G3139 has not been justified in cancer therapy due to modest or absent effects. But, surprisingly, some of its off-target effects may represent useful therapeutic principles. Therefore, antisense uptake improvements and new design of the oligonucleotide may provide us with useful therapeutics, including both the targeted gene and new anticancer mechanisms. This may be another example of how targeted therapy molecules evolve into multimodality drugs when moved from laboratory bench to bedside use, and illustrate our limited ability for target prediction and scant understanding of biological systems when designing therapeutic strategies.