Cigarette smoking, the major preventable cause of illness and death in a developed country, is a primary contributor to mortality of various malignancies such as cardiovascular and other respiratory disease. Acrolein, an important fraction of cigarette smoke (CS) gas phase and also a product of lipid peroxidation in vivo, has been demonstrated to be a mitochondrial toxicant that evokes mitochondrial impairment in isolated liver mitochondria. CS causes mitochondrial respiratory dysfunction, which results in mitochondrial membrane potential (MMP) collapse and reduces adenosine triphosphate (ATP) generation. CS can obstruct mitochondrial respiratory chain and induce necrosis in lung epithelial cells. Thus, mitochondrial dysfunction and alteration in the ATP synthesis are critically involved in pulmonary disease. Some investigation on human peripheral lymphocytes showed that CS is able to affect mitochondria through induction of oxidative stress. Investigation in cigarette-related cancer showed that mtDNA damage can be the main culprit.