Hypercholesterolemia is one of the main risk factors for the development of atherosclerosis. Decades of research have shown that lower cholesterol is better, but how low should we go? The average low-density lipoprotein cholesterol (LDL-C) level in the untreated western population is approximately 130 mg/dl. However, insights from the early phase of life in animals and humans suggest that adult humans were genetically designed for much lower lipids level than is currently considered 'average'. Adult animals in the wild and more primitive contemporary human societies share diets that are low in fats, and have similar very low blood cholesterol levels. Furthermore, extrapolation of data from meta-analyses of large trials suggest that the incidence of cardiovascular events would approach zero if the LDL-C were <60 mg/dl in primary prevention and approximately 30 mg/dl in secondary prevention. Such goals, which are considerably lower than the recommendations in current guidelines, might be attainable with the use of newer more potent lipid-lowering therapies. To date, achieving such low lipid levels appears safe, but the generalizability of these findings to broader populations and the clinical benefit on the reduction of cardiovascular complications remains to be proven.