Neuropsychological (NP) testing is now recognized as an important method for evaluating treatment effects. However, there are limitations to how these tests are currently used in most drug treatment protocols. Changes in cognition are typically defined in statistical terms, with little knowledge as to whether the observed differences are meaningful in any other sense. Methods for assessing changes in test scores need to account for test-retest reliability, practice effects, regression to the mean, and the impact of initial performance. All of these factors may vary according to the individual characteristics of the subject. This article reviews two methods from the NP literature that have attempted to account for these sources of test-retest bias. The reliable change index provides a confidence interval for predicted change by taking into account the test-retest reliability of the measure. Standardized regression-based measures use a more sophisticated statistical approach that enables them to better account for other potential sources of confound. Use of this methodology has been limited to studies of epilepsy surgery and sports-related concussion. These methods have the potential for enhancing the interpretation of NP test data in drug treatment protocols by providing an empirically based definition of clinically meaningful change.