Graft failure occurs in a sizeable proportion of coronary artery bypass conduits. We herein review relevant current evidence to give an overview of the incidence, pathophysiology, and clinical consequences of this multifactorial phenomenon. Thrombosis, endothelial dysfunction, vasospasm, and oxidative stress are different mechanisms associated with graft failure. Intrinsic morphological and functional features of the bypass conduits play a role in determining failure. Similarly, characteristics of the target coronary vessel, such as the severity of stenosis, the diameter, the extent of atherosclerotic burden, and previous endovascular interventions, are important determinants of graft outcome and must be taken into consideration at the time of surgery. Technical factors, such as the method used to harvest the conduits, the vasodilatory protocol, the storage solution, and the anastomotic technique, also play a major role in determining graft success. Furthermore, systemic atherosclerotic risk factors, such as age, sex, diabetes mellitus, hypertension, and dyslipidemia, have been variably associated with graft failure. The failure of a coronary graft is not always correlated with adverse clinical events, which vary according to the type, location, and reason for failed graft. Intraoperative flow verification and secondary prevention using antiplatelet and lipid-lowering agents can help reducing the incidence of graft failure.