Over 30 years ago, bile acid sequestrants (BAS) were among the first drugs approved to lower cholesterol levels. For over 10 years, BAS have been known to reduce glucose levels. Most importantly, BAS have been shown in outcomes studies to reduce cardiovascular events. Because they are true nonsystemic agents, BAS are generally safe and not associated with serious systemic adverse experiences. Despite their proven atherosclerotic coronary heart disease (CHD) benefits, and irrespective of their favorable effects on major CHD risk factors (hypercholesterolemia and hyperglycemia), BAS are not among the more frequently used drug treatments for hypercholesterolemia, even in patients with type 2 diabetes mellitus. Recent "high-profile" findings of investigational and approved lipid-altering and antidiabetes drug therapies illustrate that drug-induced improvements in lipid and glucose levels do not always reduce CHD risk. It may therefore be time to reconsider the clinical use of BAS. This review focuses on the recent lessons learned, and the potential mechanisms involved in efficacy and safety issues raised with torcetrapib and rosiglitazone with analogies related to the use of BAS therapy. Known and proposed mechanisms of how BAS may improve lipid and glucose levels are discussed, which are effects that may help explain how BAS reduce CHD risk. Improved tolerability of newer BAS (eg, colesevelam hydrochloride) and a "new" appreciation of the historic benefits of these "old" therapeutic agents may lead to an increased treatment role for these drugs, particularly in hypercholesterolemic patients with type 2 diabetes mellitus.