Myocardial infarction is the most common cause of cardiac morbidity and mortality in many countries. Several cytokines including G-CSF and erythropoietin have already demonstrated beneficial effects on cardiac remodeling after myocardial infarction [1–4]. In an experimental setting G-CSF improved cardiac function and mortality after myocardial infarction in mice, possibly by unknown regenerative process including the induction of proliferation, survival and differentiation of hematopoietic cells, as well as mobilization of bone marrow cells. Although bone marrow cells were claimed to differentiate into cardiomyocytes and vascular cells, thereby contributing to regeneration of myocardium and angiogenesis in ischemic hearts, accumulating evidence has questioned this concept [5]. Conversely, there is emerging evidence for other molecular mechanisms of G-CSF such as enhanced activation of Stat3 in the infarcted heart [6]. The role of G-CSF-induced Stat3 activation was investigated in transgenic mice with expression of dominant-negative Stat3 in cardiomyocytes under the control of the !-myosin heavy chain promoter (dnStat3-Tg). Administration of G-CSF was started at the time of coronary artery ligation until day 4 (Tg-G mice), while a control group of dnStat3-Tg mice given myocardial infarction received saline (Tg-cont). In this setting G-CSF resulted in smaller infarcts and less left ventricular remodeling at two weeks. The beneficial effects of GCSF on cardiac function were dose dependent and most pronounced with early undelayed treatments [6]. Takahama et al. investigated the acute effects of a clinical relevant dose of G-CSF on ischemia/reperfusion injury including both lethal arrhythmia and infarct size in canine hearts in a setting likely to simulate the human infarction reperfusion setting. For proof of concept intracoronary administration of wortmannin (WTMN), a PI3K inhibitor, was selectively administered into the infarct artery (1.5 2g/kg/min) for 60 min after the onset of reperfusion (GCSF + WTMN group, n = 7) with the effect of counteracting the antiapoptotic effects of phosphorylation and enhanced expression of Akt proteins [7]. Moreover, suppression of ventricular tachycardias by G-CSF is a novel aspect of this interesting study [7] and has been recently demonstrated for the combination of G-SCF/SCF; inducibility of ventricular tachycardias during programmed stimulation was reduced 5 weeks after G-CSF/SCF treatment. G-CSF/SCF increased cardiomyocyte diameter, arteriogenesis, and expression of connexin43 in the border zone of the infarction [8]. In summary the group of Takahama could elegantly demonstrate in a vivo model that acute cardioprotective effects of G-CSF applicated in a clinical dose at the onset of reperfusion relies on the PI3K/Aktpathway. Unfortunately, the potential risk of aggravated instent restenosis rate [9] by G-CSF was not investigated in this study. But there is mounting evidence that GCSF accelerates reendothelialization and inhibits neointimal thickening after vascular injury [10, 11]. In parallel, clinical studies on safety and feasibility of G-CSF in acute myocardial infarction have surfaced [12–16]. Considering those encouraging findings, the application of G-CSF in a reperfusion setting could be a non-invasive option to ameliorate post-infarction remodelling. Although this approach is very promising it is still a far way. We need further investigation to clarify the molecular targets of signallings activated by G-CSF and in parallel the scrutiny of double-blinded Cardiovasc Drugs Ther (2006) 20: 155–156 DOI 10.1007/s10557-006-8799-0