This article provided a scientific basis for determining whether liver hypertrophy, a common change in the liver induced by xenobiotics in toxicological studies, is an adaptive or adverse event. To maintain homeostasis in the whole organism, the liver frequently responds to xenobiotic exposure by increasing metabolic capacity via nuclear receptor activation. The resuiting hepatic adaptive responses (hepatocellular hypertrophy and increased relative liver weight) are potentially beneficial to the organism in providing increased capacity to respond to chemical-induced stress. However, excessive responses should be recognized as adverse. Practically, hepatocellular hypertrophy leading to the following alterations should be considered adverse: 1) hepatocellular degeneration/ necrosis, whether or not accompanied with inflammatory reaction, 2) changes indicating damage to biliary tracts, 3) disruption of fat metabolism, 4) pigmentation, 5) deviation from typical localization or morphological features of hypertrophied hepatocytes.