Despite significant progress in pharmacologic treatment aimed at lowering low-density lipoprotein cholesterol to reduce cardiovascular disease risk, a number of patient groups that often prove difficult to treat remain. Patients with familial hypercholesterolemia may go undiagnosed and untreated or, despite treatment, have persistently elevated lipid levels that confer a high cardiovascular disease risk. Although the true prevalence is unknown, statin intolerance is a common clinical presentation that is difficult to assess and frequently leads to suboptimal lipid treatment. Additionally, some patients may not achieve the expected response to guideline-based therapy. For all 3 groups, a standardized approach offers the best chance for effective diagnosis and optimal treatment.