The clinical importance of lowering of total cholesterol and low-density lipoprotein cholesterol (LDL-C) to decrease cardiovascular (CV) risk has been verified over many years starting with significant support in 1984 of the then previous lipid hypothesis. Significant support of this hypothesis began that year with publication of the Lipid Research Clinic study. Since then, multiple other studies including outcomes studies have established the value of LDL-C reduction in decreasing CV risk. In addition, multiple other factors such as inflammation, endothelial dysfunction, nitric oxide, antioxidant properties, and plaque stabilization appear important for modifying CV risk and possible favorable alterations by medications such as statins must be considered. Nevertheless, reduction of LDL-C has well-established value and is being accepted by clinicians as a major guideline for CV disease prevention. However, there are still problems with adherence by many clinicians to CV risk modification. Therefore, abandoning LDL-C reduction as a target, as has been advocated by some, appears premature and contraindicated. A strategy of LDL-C reduction in no way interferes with increased understanding of the complexities of atherosclerosis and new approaches to CV disease prevention as they become supported by outcomes studies.