Lipid risk factors for cardiovascular disease depend in part on lifestyle, but optimum control of lipids often demands additional measures. Low-density lipoprotein (LDL) doubtless contributes causally to atherosclerosis. Recent human genetic findings have substantiated a number of novel targets for lipid-lowering therapy including apolipoprotein C-III, angiopoietin-like protein 3 and 4, apolipoprotein V, and ATP citrate lyase. These discoveries coupled with advances in biotechnology development afford new avenues for management of LDL and other aspects of lipid risk. Beyond LDL, new treatments targeting triglyceride-rich lipoproteins and lipoprotein(a) have become available and have entered clinical development. Biological and RNA-directed agents have joined traditional small-molecule approaches, which themselves have undergone considerable refinement. Innovative targeting strategies have increased efficacy of some of these novel interventions and markedly improved their tolerability. Gene-editing approaches have appeared on the horizon of lipid management. This article reviews this progress offering insight into novel biological and therapeutic discoveries, and places them into a practical patient care perspective.