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The unbound fraction of a drug in plasma can profoundly influence both its pharmacokinetics and pharmacodynamics. For most drugs, the unbound fraction is relatively constant across the clinically relevant range of concentrations in a given individual. Nonlinear plasma protein binding involving saturation of binding sites results in increasing unbound fraction as the concentration of the drug increases, a phenomenon that is consistent with the law of mass action and is well recognized. Not widely appreciated is that some drugs undergo atypical concentration-dependent binding to plasma proteins, whereby the unbound fraction decreases with increasing concentration. In this article we review the drugs for which atypical nonlinear plasma protein binding has been reported. For each drug, the evidence for the phenomenon is presented and the proposed mechanism discussed. Also reviewed are the potential implications of atypical nonlinearity in plasma protein binding. Highlighted is the importance of understanding the relationship between unbound fraction and plasma drug concentration during the preclinical and early clinical stages of drug development, and during the routine clinical use of a drug especially if therapeutic drug monitoring is used to assist in optimization of the dosing regimen. The lesson is that the unexpected concentration-dependent behavior that has been observed for a number of drugs should be expected to occur for some other drugs.