The use of combination therapy is an effective way to manage dyslipidemia in patients with coronary artery disease (CAD). However, combination therapy is not a frequently used strategy in the treatment of CAD. Aggressive lipid-altering therapy often requires the use of combination therapy involving statins in conjunction with niacin, fibric-acid derivatives, ezetimibe, or bile acid resins. Yet, safety concerns regarding the combination of statins with other lipid-altering drugs and patient acceptance of combination therapy have influenced its application in the treatment of CAD. This article discusses several safety and regulatory considerations for the use of combination therapy for dyslipidemia.