Myelodysplastic syndromes (MDS) are characterized by refractory cytopenias due to ineffective hematopoiesis in the marrow. Cytokines play an important role in the regulation of hematopoiesis; dysregulation of their levels can lead to hematopoietic failure. Considerable evidence implicates tumor necrosis factor alpha, transforming growth factor beta, interferons, interleukin 1beta, vascular endothelial growth factor (VEGF), and other inhibitory cytokines in the pathogenesis of MDS. These cytokines are produced by the interactions between the MDS clone and the bone marrow microenvironment. Therapeutic strategies therefore may augment the action of stimulatory growth factors or disrupt the effects of myelosuppressive cytokines. Erythropoietin alone and in combination with low-dose granulocyte colony-stimulating factor can lead to erythroid responses in selected patients. Agents targeting inhibitory cytokines include thalidomide, lenalidomide, etanercept, infliximab, VEGF receptor inhibitor PTK-787, antithymocyte globulin, and SCIO-469, a p38 mitogen-activated protein kinase inhibitor. Given the biologic heterogeneity of MDS, no single treatment is effective for all patients with the disease. With more detailed knowledge of cytokine signaling cascades, coupled with technological improvements in genomics and proteomics, the future treatment of this challenging disease may lie in combination therapies customized for relevant biologic effectors.