Recent discoveries of microRNAs (miRNAs) that control high-density lipoprotein abundance and function have expanded our knowledge of the mechanisms regulating this important lipoprotein subclass. miRNAs have been shown to regulate gene networks that control high-density lipoprotein biogenesis and uptake, as well as discrete steps in the reverse cholesterol transport pathway. Furthermore, high-density lipoprotein itself has been shown to transport miRNAs selectively in health and disease, offering new possibilities of how this lipoprotein may alter gene expression in distal target cells and tissues. Collectively, these discoveries offer new insights into the mechanisms governing high-density lipoprotein metabolism and function and open new avenues for the development of therapeutics for the treatment of cardiovascular disease.