There are a number of effective but highly toxic drugs that exhibit a narrow therapeutic index and marked intersubject variability in pharmacokinetics (PK). Examples of these drugs included digoxin, theophylline, aminoglycosides, and anticancer (methotrexate) and immunosuppressive agents (cyclosporin A and FK-506). Optimal therapy with such drugs requires therapeutic drug monitoring (TDM) in order to safely obtain the desired clinical effects. The success of concentration-guided therapy with these drugs underscores the importance of using TDM and pharmacodynamic response (PD) to establish an appropriate balance of efficacy and toxicity through individualization of dosing. Although dose control has been the traditional paradigm for defining efficacy, safety, and dose response, it has recently been proposed that a concentration-oriented strategy of drug evaluation may facilitate the discovery of optimal doses and expedite new drug approval. However, as in medical therapeutics, the implementation of concentration-guided drug development may add to the complexity and cost. Therefore, it is important to assess the relative merits and limitations of dose-response and concentration-response (CR) strategies for establishing rational dosage information (e.g., a useful therapeutic range). Critical factors that have an effect on the ability to characterize dose-response/concentration-response relationships in clinical trials include study design, compliance, method of analysis, and sources of pharmacologic (PK-PD) variability. In this report, we describe the state of the art, based on a selected survey of successful dose-response studies. We give an example of a promising alternative strategy for evaluating CR for an immunosuppressive drug (FK-506) based on target drug concentrations extrapolated from preclinical models.