Hepatic injury remains not only the commonest reason for the termination of drugs in their pre-clinical development but is also the most frequent reason for the withdrawal of approved drugs from the market. Mitochondria are the central point where the different signals responsible for initiating hepatocyte cell death converge, irrespective of whether the cells ultimately die by apoptosis, necrosis (oncosis) or autophagic cell death. These signals can be in the form of direct damage to the mitochondria leading to permeability transition or can act indirectly through activation of death receptors and downstream pro-apoptotic Bcl-2 family proteins. This paper reviews our current knowledge about how hepatotoxic drugs, whether direct acting or through induction of steatosis or cholestasis, target mitochondria and cause hepatic injury.