The major purpose of therapeutic drug monitoring is to enable drug dosage individualization for differences among patients in rates of drug metabolism and/or excretion. The standard analytical methods for measuring concentrations of drugs in plasma determine drug bound to plasma proteins as well as free drug dissolved in plasma water. For this reason, the relationship between total drug concentration in plasma and treatment outcome (i.e. toxicity and efficacy) will only be good if the degree of plasma protein binding of the agent is constant, or if so little drug is protein bound that changes in binding make insignificant changes in unbound concentration. A review of available literature data indicates that, in general, protein binding of anticancer drugs is not of principal clinical relevance. However, there are several instances, in which monitoring of unbound concentrations might be useful: (i) agents demonstrating protein-concentration-dependent binding, (ii) agents that bind irreversible or near covalently, (iii) when formulation excipients modulate unbound drug levels, and (iv) metabolically interconvertible agents. While available evidence suggests that for these agents unbound drug levels correlate better with clinical effects than total plasma concentrations, there are insufficient data to justify the recommendation of the routine use of unbound drug concentration monitoring for any of these agents at present.