Cytokines exert multiple biological functions through binding to their specific receptors that triggers activation of intracellular signaling cascades. The cytokine-mediated signals may produce variable and even opposing effects on different cell types, depending on cellular context that is also dictated by the differentiation stage of the cell. Multiple myeloma (MM) is a monoclonal proliferative disorder of human plasma cells. Myeloma cells appear to include mixed subpopulations in accordance with the expression of their surface antigens, such as CD45. Although interleukin-6 (IL-6) is widely accepted as the most relevant growth factor for myeloma cells, only a few subpopulations of tumor cells, such as CD45(+) immature cells, proliferate in response to IL-6. The activation of both signal transducer and activator of transcription (STAT) 3 and extracellular signal-regulated kinase (ERK) 1/2 is not sufficient for IL-6-induced proliferation of myeloma cells that requires the src family kinase activation associated with a rapid translocation of CD45 to lipid rafts. The CD45 expression renders myeloma cells competent for not only mitogenic but also apoptotic stimuli, resulting in either proliferation or apoptosis of CD45(+) myeloma cells dependently upon the circumstantial stimuli. In contrast, in CD45(-) myeloma cells highly expressing IL-6 receptor alpha chain (IL-6Ralpha), IL-6Ralpha and insulin-like growth factor (IGF)-I receptors exist on plasma membrane in close proximity, facilitating efficient assembly of two receptors in response to IL-6. The synergistic effects of IL-6Ralpha on IGF-I receptor-mediated signals provide a novel insight into a Jak-independent IL-6 signaling mechanism of receptor cross talk in human myeloma cells. Furthermore, the signaling cross talk between the cytokine receptor, IL-6Ralpha/gp130 and the growth factor receptor tyrosine kinase, fibroblast growth factor receptor (FGFR) 3 appears in myeloma cells carrying t(4;14)(p16.3;q32). In this review we propose several mechanisms of the IL-6-induced cell proliferation that is strictly dependent upon the cellular context in myelomas.