Many medications with sedative, anxiolytic, analgesic, or stimulant properties have the potential to be inappropriately used. However, because these substances have beneficial effects, many issues pertinent to understanding prescription drug misuse may differ from those associated with other misused substances. There is currently a lack of consensus about what constitutes prescription misuse and a wide range of operational criteria have been proposed. Inappropriate medication use is frequently defined on the basis of user characteristics (i.e. any non-prescribed use), the reason for use (i.e. use for recreational purposes), the presence of clinically significant symptoms (i.e. meeting diagnostic criteria for abuse and dependence) or on the presence of any of these factors. In cases where multiple criteria are used to define misuse there is often a lack of differentiation among them, while studies that use more specific criteria tend to exclude certain types of misuse from consideration altogether. In addition, in some cases there are a number of potential ways that a single operational criterion can be met and many of these may be associated with substantially different risks, harms, and predictors. Due to considerable variability in the classification of medication misuse both within and between studies, it is currently difficult to interpret the clinical significance of existing findings or to determine the true magnitude of problems associated with any particular form of misuse. In the present review many of the problems and challenges for adequately defining prescription drug misuse will be overviewed and recommendations will be made on how to better characterize this phenomenon.