Proposed applications of increasingly sophisticated biologically-based computational models, such as physiologically-based pharmacokinetic models, raise the issue of how to evaluate whether the models are adequate for proposed uses, including safety or risk assessment. A six-step process for model evaluation is described. It relies on multidisciplinary expertise to address the biological, toxicological, mathematical, statistical, and risk assessment aspects of the modeling and its application. The first step is to have a clear definition of the purpose(s) of the model in the particular assessment; this provides critical perspectives on all subsequent steps. The second step is to evaluate the biological characterization described by the model structure based on the intended uses of the model and available information on the compound being modeled or related compounds. The next two steps review the mathematical equations used to describe the biology and their implementation in an appropriate computer program. At this point, the values selected for the model parameters (i.e., model calibration) must be evaluated. Thus, the fifth step is a combination of evaluating the model parameterization and calibration against data and evaluating the uncertainty in the model outputs. The final step is to evaluate specialized analyses that were done using the model, such as modeling of population distributions of parameters leading to population estimates for model outcomes or inclusion of early pharmacodynamic events. The process also helps to define the kinds of documentation that would be needed for a model to facilitate its evaluation and implementation.