Many studies have characterized the role of growth factors in multiple myeloma (MM) pathogenesis and have derived novel therapies to improve patient outcome based upon targeting cytokines and their signaling cascades both in the MM cell and in the bone-marrow (BM) microenvironment. These cytokines include interleukin 6 (IL-6), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), stromal cell-derived factor 1alpha (SDF-1alpha), IL-21, B-cell stimulating factor 3 (BSF-3) and fibroblast growth factor (FGF). These cytokines are secreted from stromal cells (SCs), endothelial cells and/or osteoclasts, and promote MM cell growth, survival and migration, as well as paracrine cytokine secretion and angiogenesis in the BM milieu. Thus inhibition of signaling cascades induced by these cytokine provides rationale for a therapeutic option for MM.