The discovery that elevated total cholesterol levels and the subsequent understanding that low-density lipoprotein cholesterol levels are associated with higher risk for cardiovascular disease (CVD) has led to the development of lipid management strategies that seek to reduce the burden of CVD. Although substantive progress has been made in reducing death and cardiovascular events, questions remain regarding the optimal approach to further reduce CVD-associated death and disability. Based on current evidence, statins are the clear first-line agents for the management of hyperlipidemia in patients at high risk for cardiovascular events. However, due to the failure of recent clinical trials evaluating antihyperlipidemic drugs, the most appropriate lipid management strategy in patients who cannot tolerate statin therapy or who warrant antihyperlipidemic therapies in addition to statins is a major therapeutic controversy. In this review, we summarize the clinical trial evidence evaluating the efficacy of second-line antihyperlipidemic drug classes for reducing cardiovascular risk, provide recommendations for appropriate use of nonstatin lipid-altering drugs, and identify key areas of future research to support evidence-based lipid management. Given the complexity, magnitude, and burden of CVD, opportunities to improve processes of care and identify new therapeutic options clearly exist.