—The benefit of cholesterol-lowering therapy in the prevention of coronary heart disease (CHD) is well established. The secondary prevention Scandinavian Simvastatin Survival Study (4S) and the primary prevention West of Scotland Coronary Prevention Study (WOSCOPS) demonstrated that lipid lowering with a statin can dramatically and cost-effectively reduce CHD morbidity and mortality with no increase in noncardiovascular mortality. The Cholesterol and Recurrent Events (CARE) trial extended benefit to CHD patients without high cholesterol. Post hoc analyses of data from these large trials are contributing to speculation, driven by subset analyses and meta-analyses, about whether cholesterol intervention should be target based, as current guidelines recommend. Whereas CARE data support the importance of baseline LDL cholesterol (LDL-C), with greatest clinical event risk reduction in the upper part of the LDL-C range in the trial, 4S found no difference in outcome according to baseline LDL-C in a quartile analysis, and WOSCOPS found no linear relation between decrease in LDL-C and decrease in relative risk for CHD. Furthermore, WOSCOPS showed no additional clinical benefit with LDL-C lowering beyond ≈24%. Questions raised by such analyses require answers from prospective, hypothesis-based data, and at present there is no compelling argument for moving away from LDL-C targets. The hypothesis-based findings of 4S, CARE, and WOSCOPS support current clinical guidelines, and lowering LDL-C may reduce risk more substantially than might have been predicted.