Cellular swelling has emerged as an important initiator of metabolic and proliferative changes in various cells. Because of the unique regenerative capacity of the adult liver, researchers have delineated key intracellular signals that are activated following mitogens, injury, and partial hepatectomy. Although hepatocellular swelling is commonly observed following these regenerative stimuli, only recently has the relationship between cell volume increase and proliferative activity been investigated; to date, the data implicating cell volume increase with hepatocyte regeneration has been mostly indirect. Hepatocyte swelling has been demonstrated in various clinical scenarios from sepsis, hepatic resection, ischemia-reperfusion injury, glucocorticoid excess, and hyperinsulinemia. Using various in vivo and in vitro models of hepatocyte swelling, particularly hypo-osmotic stress, investigators have demonstrated changes in cellular structure: (1) cell membrane stretch, (2) cytoskeletal microtubule and microfilament reorganization, and (3) alterations in cytoskeletal-membrane complexes. Similar studies have demonstrated a causal relationship between cell volume increase and intracellular signals: (1) activation of cytoplasmic signaling cascades such as MAPKs, PI-3-K, and PKC, (2) activation of proliferative transcription factors NF-κB, AP-1, STATs, C/EBPs, and (3) transcription of metabolic and immediate early genes of regeneration. Through mechanotransduction, or the translation of physical changes to chemical signals, cell volume is a potent effector of these signaling events. Growing evidence demonstrates a link between these physical and chemical changes in the swelling-mediated growth in the liver. ©2001 Wiley-Liss, Inc.