Stem cell factor (SCF), an essential growth factor in normal hematopoiesis, exerts potent effects when combined with cytokines. In particular, its synergy with granulocyte colony-stimulating factor (G-CSF) results in important biologic responses. These include enhancement of ex vivo long-term expansion of human primitive hematopoietic cells and increased mobilization of peripheral blood progenitor cells (PBPC) for transplantation. Despite the clinical importance of the interaction between SCF and G-CSF, the absence of a model system in which it could be studied at the cellular level had impaired the ability to understand the basis of their co-operation. To overcome this impediment, a system was recently generated which recapitulates the biologic synergy between SCF and G-CSF. MO7e-G cells have allowed the identification of key events in the synergistic actions of these cytokines on proliferation and gene expression. Among the biochemical and molecular events mediated by these cytokines are the down-regulation of p27kip1 and the independent phosphorylation of STAT3 on tyrosine and serine residues. Recent work has provided increasing evidence for the clinical importance of the combination of SCF and G-CSF. The elucidation of the intracellular events triggered by their receptors is now shedding light on key mediators of their synergistic effects. The identification of these pathways is of considerable importance for understanding fundamental aspects of hematopoiesis, and as potential targets for therapeutic intervention.