For about half a century, the binding of drugs to plasma albumin, the "silent receptor," has been recognized as one of the major determinants of drug action, distribution, and disposition. In the last decade, the binding of drugs, especially but not exclusively basic entities, to another plasma protein, alpha 1-acid glycoprotein (AAG), has increasingly become important in this regard. The present review points out that hundreds of drugs with diverse structures bind to this glycoprotein. Although plasma concentration of AAG is much lower than that of albumin, AAG can become the major drug binding macromolecule in plasma with significant clinical implications. Also, briefly reviewed are the physiological, pathological, and genetic factors that influence binding, the role of AAG in drug-drug interactions, especially the displacement of drugs and endogenous substances from AAG binding sites, and pharmacokinetic and clinical consequences of such interactions. It can be predicted that in the future, rapid automatic methods to measure binding to albumin and/or AAG will routinely be used in drug development and in clinical practice to predict and/or guide therapy.