Statins (HMG-CoA reductase inhibitors) are first-line agents for the management of hyperlipidemia in patients at high risk of cardiovascular events and their use for cardiovascular disease prevention is clearly supported by clinical evidence. Although safe and generally well tolerated, there is growing evidence to suggest that statins are associated with an elevated occurrence of new-onset diabetes mellitus. The incidence of this adverse effect is not negligible, especially for specific subsets of patients. Statins remain the cornerstone for primary and secondary cardiovascular prevention, but specific attention to glucose metabolism and metabolic syndrome features should be given before and during statin treatment, especially in cohorts at greater risk, and a potential tailored statin treatment based on the patient's cardiovascular and metabolic risk profile might emerge as the safest therapeutic approach. The main purpose of this review is to discuss the clinical evidence regarding the association of statin use with new onset diabetes mellitus, the cardiovascular benefit/risk ratio with statins, and the rationale for individualized statin therapy. Future trials with adequate and long follow-up designed to assess the benefit/risk ratio of a specific statin will further refine the basis of this strategy.