While statins have formed the cornerstone of strategies for cardiovascular prevention, the residual risk related to low-density lipoprotein cholesterol (LDL-C) and other lipoprotein factors provides a landscape for development of new therapies. However, a number of lipid-modifying therapies have failed to reduce cardiovascular event rates in contemporary clinical trials of statin-treated patients. The factors considered in outcome measure selection for clinical trials of novel lipid-lowering therapies are reviewed. Evaluation of lipid-modifying drugs in clinical trials spans a spectrum from their effects on conventional circulating lipid parameters through to their impact on atherosclerotic plaque and ultimately clinical outcomes. The design of these trials has an important impact on the result and ultimate interpretation of these studies.