Low-density lipoprotein cholesterol (LDL-C) is recognized as one of the major risk factors for cardiovascular disease. Many interventions ranging from diet to bile acid sequestrants, cholesterol absorption inhibitors and statins reduce LDL-C levels; most have been shown to reduce cardiovascular events. Current intestinally-acting agents reduce LDL-C by 15–20%, while statins reduce LDL-C by up to 50%. All these therapies show marked variations in individual response, and the management of ‘drug-resistant’ patients is an increasing challenge. In addition, many patients cannot tolerate sufficient statin doses, while intestinal agents have less efficacy and so cannot reach the LDL-C targets that are now desirable. Thus, the opportunity exists for additional agents, taken synergistically with current drugs that could help reduce LDL-C to the eventual target of 1 mmol/l in patients with atherosclerosis. This review summarizes new developments in the field of novel agents to lower LDL-C.