Ischemia-reperfusion (I/R) associated with hepatic resection and living related liver transplantation is an unsolved problem in clinical practice. Indeed, I/R induces damage and regenerative failure in clinical liver surgery. Signaling pathways regarding the pathophysiology of liver I/R and regeneration making clear distinction between situations of cold and warm ischemia, as well as liver regeneration with or without vascular occlusion, will be addressed. The different experimental models used to date to improve the postoperative outcomes in clinical liver surgery will be also described. Furthermore, the most updated therapeutic strategies, as well as the clinical and scientific controversies in the field, will be discussed. Such information may be useful to guide the design of better experimental models as well as the effective therapeutic strategies in liver surgery that can succeed in achieving its clinical application.