Elevated low-density lipoprotein cholesterol (LDL-C) levels are a major modifiable risk factor for cardiovascular disease (CVD). In addition, treatment with statins reduces cardiovascular morbidity and mortality both in patients without and with established CVD. However, there still exist unresolved issues in the management of dyslipidemia. First, which are the optimal LDL-C levels? Second, do low high-density lipoprotein cholesterol (HDL-C) levels play a role in the pathogenesis of atherosclerosis and should they also represent treatment targets? In the present review, we discuss these two pertinent questions. Accumulating data, both from observational studies and from interventional studies with statins and other lipid-lowering agents, suggest that lowering LDL-C levels considerably below the currently recommended targets is both safe and further reduces cardiovascular morbidity and mortality. These benefits are particularly relevant for patients at very high cardiovascular risk, i.e. those with established CVD. On the other hand, it is questionable whether HDL-C is causally related to atherosclerosis and whether increasing HDL-C levels will translate into reduced cardiovascular risk. This uncertainty is even more pronounced in patients who achieve very low LDL-C levels with statin treatment.