Ezetimibe is the first lipid-lowering drug which selectively inhibits the intestinal uptake of dietary and biliary cholesterol by binding to the cholesterol transporter protein Niemann-Pick C1 Like 1 (NPC1L1). This drug is an effective new tool for cholesterol lowering and allows to better investigate the mechanisms involved in cholesterol absorption by small intestine. Ezetimibe is rapidly absorbed after oral administration and extensively metabolized ( > 80%) to the pharmacologically active ezetimibe-glucuronide compound; furthermore, it shows a favourable drug-drug interaction profile due to the absence of clinically relevant interactions with a variety of drugs commonly used in patients with hypercholesterolemia (in particular, statins, fibrates and nicotinic acid). In primary hypercholesterolemia, ezetimibe alone reduces low density lipoprotein (LDL) cholesterol by about 18% and induces an additional 25% reduction when added to on-going statins. The combination therapy of ezetimibe with statins or fibrates is effective and safe also in patients affected by the Metabolic Syndrome, which is characterized by complex lipid alterations, including increased triglyceride levels, low high density lipoprotein (HDL) cholesterol concentrations, preponderance of small dense LDL particles and post-prandial hyperlipidemia. In this review, we considered the main studies evaluating the rationale and the efficacy of therapy with ezetimibe alone or in combination with other lipid-lowering drugs, in order to provide clinical indications.