In this study, we review current knowledge regarding molecular pathways activation and their possible mechanisms in the perioperative period of coronary artery bypass surgery (CABG). We also highlight the role of off-pump CABG as a possible way to better understand these biological changes.We show that, after both on-pump and off-pump CABG, there is a marked and protracted activation of several molecular pathways indicating increased inflammatory status, haemostasis activation, as well as increased oxidative stress and unfavourable endothelial milieu. These changes persist for days and even weeks after surgery. Interestingly, a relatively limited number of these pathways show a more pronounced activation in case of cardiopulmonary bypass use, and these markers are mainly associated with oxidative stress activation; on the contrary, the vast majority of the pathways has a similar course both in on and off-pump procedures. Surgical stress accounts for more protracted and marked molecular pathway perturbations overall, being the effect of cardiopulmonary, if any, limited to the very early hours after surgery. The near future of the translational research in coronary bypass surgery is to develop therapeutic strategies aimed at reducing this response, that is largely unrelated to cardiopulmonary bypass use, in order to reduce perioperative complications and to speed up patients' recovery.