This Focus Issue on dyslipidaemias contains a State of the Art Review article entitled ‘How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol’ by Angelos Karagiannis from Emory University School of Medicine in Atlanta, GA, USA, and colleagues.1 The authors note that LDL cholesterol (LDL-C) is a proven causative factor for developing atherosclerotic cardiovascular disease (CVD), and its reduction substantially reduces cardiovascular risk.2–4 Individuals with genetic conditions associated with lifelong very low LDL-C levels can be healthy. We now possess the pharmacological armamentarium [statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors] to reduce LDL-C to an unprecedented extent. Increasing numbers of patients are expected to achieve very low (<30 mg/dL) LDL-C. Cardiovascular event reduction increases log linearly in association with lowering LDL-C, without reaching any clear plateau even when very low LDL-C levels are achieved. It is still controversial whether lower LDL-C levels are associated with significant clinical adverse effects (e.g. new-onset diabetes mellitus and possibly haemorrhagic stroke), and long-term data are needed to address safety concerns. This review presents the familial conditions characterized by very low LDL-C, analyses trials with lipid-lowering agents where patients attained very low LDL-C, and summarizes the benefits and potential adverse effects associated with achieving very low LDL-C. Given the potential for cardiovascular benefit and the short-term safety profile of very low LDL-C, it may be advantageous to attain such low levels in specific high-risk populations. Further studies are needed to compare the net clinical benefit of non-LDL-C-lowering interventions with very low LDL-C approaches, in addition to comparing the efficacy and safety of very low LDL-C levels vs. current recommended targets.