The process of apoptosis plays a crucial role in several physiological as well as pathophysiological processes, and is a fundamental mechanism for the deletion of unwanted, senescent, or damaged cells. Defects in the apoptotic mechanisms or, even more, disturbances of the equilibrium between cellular replication, growth, differentiation and apoptosis favor the growth of preneoplastic and tumoral lesions in the liver. Clinical and molecular medical analyses have yielded a considerable amount of information about liver oncogenesis. Studies on transgenic models of hepatocarcinogenesis have allowed a meticulous examination of the roles of apoptosis, tumor suppressors, DNA repair processes and other events in the clonal expansion and accumulation of genetic lesions. During initiation, there is rapid proliferation and a high amount of apoptosis, whereas in the promotion stage, there is decreased cell death and increased cell proliferation. Accumulating evidence suggests a defective apoptotic process in human hepatocellular carcinoma. Moreover, a range of prognostic factors related to apoptosis might be used in the early assessment of the progress of hepatocarcinogenesis as well as in hepatocellular carcinoma recurrence. Lastly, many potential therapeutic strategies, that induce the apoptotic process in various ways, can be applied to the hepatocellular carcinoma management.