BACKGROUND: Treatments with ezetimibe/simvastatin (combined or alone) have been indicated as very promising approaches to strongly reduce cholesterol levels in hyperlipidemic patients. OBJECTIVE: We will discuss the efficacy and safety of ezetimibe/simvastatin and their potential to reduce atheroprogression. The molecular mechanisms underlying the possible benefits in atherosclerosis and its complications will also be described. RESULTS/CONCLUSIONS: Combined therapy with ezetimibe/simvastatin has been shown to improve lipid profile inducing a very rapid reduction of low-density lipoprotein cholesterol levels in clinical trials. In the near future, potential clinical benefits could be observed in the IMPROVE-IT or SHARP trials. Although clinical studies are needed to further confirm safety of ezetimibe/simvastatin therapy, the greater efficacy in lipid-lowering was not associated with the increase of adverse events. Also the possible association between ezetimibe and cancer, which was observed in the SEAS trial, was not confirmed by further studies and meta-analyses. At present, ezetimibe should be considered an effective lipid-lowering agent that can be used in conjunction with simvastatin at the beginning of therapy, or included in the treatment of patients who do not achieve their low-density lipoprotein cholesterol goal with statins alone.