—Several laboratories have demonstrated the presence of apoptotic cell death in atherosclerotic plaques. Apoptosis occurs in at least 2 stages. The final “execution” phase, which includes DNA fragmentation, is brief (≈6 hours) and irreversible and can be detected by the terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) technique. The TUNEL technique is only selective (rather than specific) for apoptotic nuclei, because these contain a far greater degree of DNA fragmentation than do nonapoptotic nuclei. Nonapoptotic cell nuclei that show high levels of RNA synthesis and splicing can also be labeled. This could explain the large variation in the reported percentages of TUNEL-positive nuclei in the plaques. Therefore, the TUNEL technique should be combined with additional techniques, such as markers of transcription and morphological criteria. Recent studies indicate that human fatty streaks differ from adaptive intimal thickenings by the presence of cells containing pro-apoptotic proteins. However, apoptotic cell death is present only in advanced atherosclerotic plaques that show a dense macrophage infiltration. This indicates that although both smooth muscle cells and macrophages within the human fatty streaks become susceptible to apoptosis, additional factors (mainly macrophage- and lipid-derived factors) are necessary to terminate the cell death pathway.