Recent evidence indicates that anti-apoptotic functions of BcI-2 can be regulated by its phosphorylation. According to the 'mitotic arrest-induced' model, multi-site phosphorylation of the BcI-2 loop domain is followed by cell death. In contrast, in cytokine-dependent cell lines, cytokines mediate phosphorylation of BcI-2 on S70, preventing apoptosis. As discussed in this review, these models are not mutually exclusive but reflect different cellular contexts. During mitotic arrest, signal transduction is unique and is fundamentally different from classical mitogenic signaling, since the nucleus membrane is dissolved, gene expression is reduced, and numerous kinases and regulatory proteins are hyperphosphorylated. Hyperphosphorylation of BcI-2 mediated by paclitaxel and other microtubule-active drugs is strictly dependent on targeting microtubules that in turn cause mitotic arrest. In addition to serine-70 (S70), microtubule-active agents promote phosphorylation of S87 and threonine-69 (T69), inactivating BcI-2. A major obstacle for identification of the mitotic BcI-2 kinase(s) is that inhibition of putative kinase(s) by any means (dominant-negative mutants, antisense oligonucleotides, pharmacological agents) may arrest cycle, preventing mitosis and BcI-2 phosphorylation. The role of BcI-2 phosphorylation in cell death is discussed.