Granulocyte colony-stimulating factor (G-CSF) and erythropoietin are two cytokines that have been demonstrated to improve cardiac function and perfusion in myocardial infarction. G-CSF was initially evaluated as a stem cell mobilizer and erythropoietin as a cytoprotective agent. However, both cytokines have direct cytoprotective effects and stem cell-mobilizing ability. Direct cytoprotective effects of both cytokines are commonly mediated by the Jak–STAT pathway. In preclinical study, G-CSF and erythropoietin improved cardiac function and perfusion by angiomyogenesis and protection of cardiomyocytes in myocardial infarction. However, results from recent clinical trials did not support beneficial effects of cytokine therapy with G-CSF or erythropoietin alone in patients with myocardial infarction. Further studies are required to elucidate the mechanism of action and to improve therapeutic efficacy by employing novel strategies, such as combined cytokines.