The essential prerequisite for regression is robust improvement in plaque milieu, meaning large plasma reductions in atherogenic apolipoprotein B-lipoproteins or brisk enhancements in ‘reverse’lipid transport from plaque into liver. Importantly, the processes of regression are consistent with rapid correction of features characteristic of the rupture-prone, vulnerable plaques responsible for acute coronary syndromes. New interventions to lower apolipoprotein B-lipoprotein levels and enhance reverse lipid transport may allow regression to become a widespread clinical goal. Strategies based on recent mechanistic insights may facilitate further therapeutic progress.