Many clinical trials and data from scientific investigations have suggested the effects of statins on high-density lipoprotein (HDL) metabolism, besides their actions in reducing low-density lipoprotein (LDL) cholesterol. These actions have been proposed as important anti-atherogenic properties that contribute to the additional reduction of risk for cardiovascular diseases. The regulation of genes involved in the reverse cholesterol transport (RCT) is very complex and the modulation exerted by statin treatment is poorly understood. In this review, we discuss the molecular mechanisms underlying the modulation of genes controlling the RCT with special emphasis on the reported tissue-specific effects of statins. The statin modulation of genes participating in the different stages of RCT (cholesterol efflux from peripheral tissues, HDL metabolism in the plasma and internalization by the liver) has been summarized. Recent reports on novel mechanisms of regulation by microRNAs are also discussed.