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Abstract: Recent guidelines in North America and Europe recommend lowering low density lipoprotein associated cholesterol (LDLC) to achieve optimal coronary heart disease risk reduction. Statins have been the therapy of choice and proven successful and relatively safe. However, we are now facing new challenges and it appears that additional or alternative drugs are urgently needed. This boosts research in the field, reopening old cases like other inhibitors of cholesterol synthesis or making attractive tools from the latest technologies like gene silencing by anti-sense oligonucleotides. LDLs are cholesterol-enriched lipoproteins stabilized by the hepatic apolipoprotein B100, and derived from TG rich very low density lipoprotein. This review focuses on the molecular pathways involved in plasma LDLC production and elimination, in particular cholesterol absorption and the hepatobiliary route, apoB100 and VLDL production, and LDL clearance via the LDL receptor. We will identify important or rate-limiting proteins (including Niemann-Pick C1-like 1 (NPC1L1), microsomal TG transfer protein (MTP), acyl-coenzyme A/cholesterol acyltransferase (ACAT), Acyl-CoA:diacylglycerol acyltransferases 2 (DGAT2), proprotein convertase subtilisin kexin type 9 (PCSK9)), and nuclear receptors (farnesoid X receptor (FXR), thyroid hormone receptor (TR)) that constitute interesting therapeutic targets. Numerous compounds already in use modulate these pathways, such as phytosterols, ezetimibe, bile acids sequestrants, niacin, and fibrates. Many pathways can be considered to lower LDLC, but the road has been paved with disappointments and difficulties. With new targets identified and diversification of the drugs, a new era for better LDLC management is plausible. [Copyright &y& Elsevier]