Although the roles of the sterol response element binding protein-1 (SREBP1) and SREBP2 transcription factors in regulating fatty acid and cholesterol synthesis and uptake have been known for some time, it was recently discovered that 2 related microRNAs (miRs), miR-33a and miR-33b, are embedded in these genes. Studies indicate that miR-33a and miR-33b act with their host genes, Srebp2 and Srebp1, respectively, to reciprocally regulate cholesterol homeostasis and fatty acid metabolism in a negative feedback loop. miR-33 has been shown to posttranscriptionally repress key genes involved in cellular cholesterol export and high-density lipoprotein metabolism (Abca1, Abcg1, Npc1), fatty acid oxidation (Crot, Cpt1a, Hadhb, Ampk), and glucose metabolism (Sirt6, Irs2). Delivery of inhibitors of miR-33 in vitro and in vivo relieves repression of these genes, resulting in upregulation of the associated metabolic pathways. In mouse models, miR-33 antagonism has proven to be an effective strategy for increasing plasma high-density lipoprotein cholesterol and fatty acid oxidation and protecting from atherosclerosis. These exciting findings have opened up promising new avenues for the development of therapeutics to treat dyslipidemia and other metabolic disorders.