The observation of mitotic figures in the epithelium of the normal gallbladder is exceptional because cell renewal is occurring at a very slow rate. It is only after using 3H-thymidine and autoradiography to observe the cells in DNA synthesis that evidence of a significant epithelial cell replication has been provided. Because numerous mitotic figures and increased 3H-thymidine uptake have been observed after intraluminal introduction of foreign bodies or after ligation of the common bile duct in animals, mechanical distension has been supposed to represent an important trigger factor of cell proliferation in this hollow organ. An increased epithelial cell renewal was also observed in human gallbladders of patients with a complete obstruction of the common bile duct causing the distension. However, the absence of correlation between the degree of gallbladder distension and the proliferative response was suggesting that factors other than distension could be involved. In studies on experimental lithiasis cell proliferation appeared to be enhanced in the gallbladder epithelium of mice fed on a cholesterol-cholic acid-rich lithogenic diet. The fact that the increase in proliferative activity was preceding the formation of gallstones was another indication that factors other than mechanical stimulation by stretching or by the stones may stimulate cell renewal in this organ. Factors in the bile of animals receiving a lithogenic diet could be involved which might cause cellular death and, hence, a regenerative reaction. Direct mitogenic effect of an unknown factor in the bile of these animals is an alternative possibility. On the other hand the stimulating effect of postprandial hormones on gallbladder cell renewal suggested by the observation of a DNA synthesis peak after feeding has been established. Synthetic cholecystokinin analogues have been shown to increase the proliferative activity and to induce epithelial hyperplasia in this organ. In one recent study using fundusectomy to increase the serum gastrin levels, a significant proliferative stimulation in the gallbladder was also observed. In human gallbladder mitotic activity in gallbladders with gallstones in much higher than in the controls. No correlation between stone number, weight or volume and the proliferative activity was put in evidence, whereas cell renewal appeared to be more influenced by the composition of the stones than by their physical presence. Epithelial DNA synthesis activity was, namely, much higher in gallbladders with cholesterol stones than in those with pigment stones. Whether increased cell turnover and, hence, cellular shedding into the lumen could represent a nucleating factor for cholesterol stones is an attractive working hypothesis. Considering the very high frequency of gallstones in man and also the frequent association of gallbladder cancer and lithiasis, further studies on mitotic activity in this organ are required. In conclusion, data from animal experiments and in vitro studies on human gallbladders indicate that gallbladder epithelial cell proliferation may be influenced by several mechanical, chemical and hormonal factors. The list of these factors is still incomplete while their possible role in gallbladder disease is a fascinating exploration field for future research.