The new Adult Treatment Panel guidelines will be published in 2011. This paper suggests the consideration of major changes in the existing management guidelines for low-density lipoprotein cholesterol management based on 2 fundamental principles: return the low-density lipoprotein cholesterol level to the normal range and begin treatment closer to disease onset. These principles suggest the value of rethinking all 3 of the principal features of the Adult Treatment Panel III guidelines for low-density lipoprotein cholesterol management: the initiation criteria, the use of variable targets, and the level of the treatment target. Because the principal issue surrounding guideline change is likely to be uncertainty concerning cost and toxicity, the text of new guidelines would have to completely satisfy this concern by strong emphasis on a prudent conservative approach to implementation and would include both cautionary data and caveats concerning the tradeoffs between the potency, cost, and toxicity of statins. The proposed changes in the guidelines, if combined with effective implementation, would likely lead to the displacement of atherosclerotic disease as the nation's number 1 killer. This review provides a logical rationale and discusses the pros and cons for each of the proposed changes.