<p>In view of the growing evidence supporting more marked reductions of low-density lipoprotein cholesterol (LDL-C), according to the concept of “the lower is better” and with the availability of powerful and well tolerated lipid-lowering drugs, physicians are facing today with the clinical management of patients with very low LDL-C levels. The fear of potential risks linked to extreme reductions of LDL-C down to very low levels may lead to the de-escalation of treatments with consequent paradoxical unfavorable consequences due to the exposure to a higher cardiovascular risk. The aim of this review is to point out evidence of very low LDL-C clinical impact, with a focus on potential adverse effects. Research on cholesterol homeostasis has identified complex mechanisms which guarantee cell functions even when circulating cholesterol levels are very low. The almost complete self-sufficiency of the human body in terms of cholesterol needs is confirmed by evidence derived from genetically determined models with very low LDL-C levels. Studies on the potential harm of lowering LDL-C to very low concentrations do not confirm an increased risk of cancer or neurodegenerative disease attributable to lipid-lowering treatments, whereas evidence suggests a potential benefit in these settings. A potential increased risk of hemorrhagic stroke has been reported, suggesting tight monitoring and control of blood pressure should be implemented in patients with very low LDL-C levels. With regard to statin treatment, a dose-dependent increased risk of newly diagnosed diabetes has been reported. This adverse effect has not been found with more recently approved lipid-lowering drugs.</p>