Abstract: Liver cell injury and cell death is a prominent feature in all liver disease processes. During the last 5–10 years, most research activities focused almost exclusively on evaluating apoptotic cell death and the corresponding intracellular signaling pathways. Although this effort led to substantial progress in our understanding of the mechanisms of apoptosis, it also created substantial confusion regarding the predominant mode of cell death and the relevance of apoptosis in a variety of liver disease models, as discussed in this review for acetaminophen and troglitazone hepatotoxicity, obstructive cholestasis and viral hepatitis. Part of the problem is related to the fact that there is no specific assay or parameter, with the exception of morphological changes in vivo, which allows the unequivocal distinction between apoptosis and oncotic necrosis. In addition, some aspects of the signaling pathways are similar. Therefore, to make progress in identifying relevant pharmacological intervention strategies to prevent or attenuate human liver disease processes, it is of critical importance to apply several different experimental approaches and analyze as many parameters as possible. In addition, positive controls for the assumed process should be used whenever possible and mechanisms of cell injury should only be investigated in model systems relevant for the human pathophysiology.