Divergent life or death responses of a cell can be controlled by a single cytokine (tumor necrosis factor alpha, TNF) via the signaling pathways that respond to activation of its two receptors (TNFR1 and TNFR2). Here, we show that the choice of life or death can be controlled by manipulation of TNFR signals. In human erythroleukemia patient myeloid progenitor stem cells (TF-1) as well as chronic myelogenous leukemia cells (K562), granulocyte-macrophage colony-stimulating factor primes cells for apoptosis. These death-responsive cells show prolonged TNF stimulation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, but no NF-kappaB transcriptional activity as a consequence of receptor-interacting protein degradation by caspases. Conversely, cells of a proliferative phenotype display antiapoptotic NF-kappaB responses that antagonize c-Jun N-terminal kinase and p38 mitogen-activated protein kinase stress kinase effects. These proliferative effects of TNF are apparently due to enhanced basal expression of the caspase-8/FLICE-inhibitory protein FLIP. Manipulation of the NF-kappaB, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinase signals switches leukemia cells from a proliferative to an apoptotic phenotype; consequently, these highly proliferative cells die rapidly. in addition, sodium salicylate mimics the death phenotype signals and causes selective destruction of leukemia cells. These findings reveal the signaling mechanisms underlying the phenomenon of human leukemia cell life/death switching. Additionally, through knowledge of the signals that control TNF life/death switching, we have identified several therapeutic targets for selectively killing these cells.