In this review, we discuss the potential expectations, validity, predictive ability, and reality of pharmacogenetics in (1) titration of medication dose, (2) prediction of intended (efficacy) drug response, and (3) dose prediction of unintended (adverse) drug response. We expound on what these potential genetic predictors tell us and, more importantly, what they cannot tell us. Although pharmacogenetic markers have been hailed as promising tools, these proclamations are based mainly on associations rather than their evaluation as predictors. To put the expectations of the promise of pharmacogenetics in a realistic perspective, we review three examples. First, warfarin pharmacogenetics, wherein although the validity of the genetic variant dose is established and there is a validity of genetic variant-hemorrhage association, the clinical utility of testing is not clear. Second, the strong and clinically relevant HLA-Stevens-Johnson syndrome/toxic epidermal necrolysis association highlights the role of ethnicity. Third, the influence of CYP2D6 on tamoxifen efficacy, a model candidate with potential clinical utility but unclear validity. These examples highlight both the challenges and opportunities of pharmacogenomics. First, establishing a valid association between a genetic variation and drug response; second, doing so for a clinically meaningful outcome; and third, providing solid evidence or rationale for improvement in patient outcomes compared with current standard of care. © 2010 Elsevier Inc. All rights reserved.