Cigarette smoking (CS) is a major health hazard particularly for the cardiovascular system and cancer. The mechanisms involved in CS-related cardiovascular dysfunction have been largely debated. CS increases inflammation, thrombosis, and oxidation of low-density lipoproteins. Recent experimental and clinical data support the hypothesis that cigarette smoke exposure increases oxidative stress as a potential mechanism for initiating cardiovascular dysfunction. Cardiac myocytes, as well as and other long-lived postmitotic cells show dramatic smoke-related alterations that mainly affect the mitochondria and lysosomal compartment. Mitochondria are primary sites of reactive oxygen species formation that cause progressive damage to mitochondrial DNA and proteins in parallel to intralysosomal lipofuscin accumulation. There is amassing evidence that various mechanisms may contribute to accumulation of damaged mitochondria following initial oxidative injury. Such mechanisms may include clonal expansion of defective mitochondria, decreased propensity of altered mitochondria to become autophagocytosed, suppressed autophagy because of heavy lipofuscin loading of lysosomes and decreased efficiency of specific proteases involved into mitochondrial degradation. A possible interplay between microtubule plasticity and oxidative stress also exists in cardiomyocytes, so this could represent another potential mechanism by which smoking induces/accelerates atherosclerosis.