In recent years, investigators have unraveled a previously unrecognized role for granulocyte colony-stimulating factor (G-CSF) in the regulation of T-cell and dendritic cell functions. The experimental evidence in favor of G-CSF-mediated immune regulation includes the ability to skew T-cell cytokine secretion to T-helper type 2 responses, and to promote regulatory T-cell and tolerogenic dendritic cell differentiation. Accordingly, beneficial effects of G-CSF have been detected in animal models of immune-mediated diseases, including posttransplantation graft-versus-host disease, experimental autoimmune encephalomyelitis, lupus nephritis, inflammatory bowel disease, and diabetes. The growing body of evidence supporting a novel role for G-CSF in the induction of T-cell tolerance is reviewed herein.