The phrase “off-label prescribing” refers to the use of medicines in ways that have not been approved by regulatory agencies. While off-label prescribing is ubiquitous, it has been a topic of significant controversy for some time. The controversy stems in large part from the realization that much off-label prescribing is not “evidence based.” This, in turn, creates ambiguity about whether using a medicine off label is equivalent to the experimental use of unlicensed investigational product or whether it should rather be considered a legitimate extrapolation from approved uses of a medicine. In this chapter, we will present the results of qualitative research investigating physicians’ perspectives of off-label prescribing. In particular, we will explore how physicians understand concepts such as evidence, experimentation, expertise, uncertainty, and reasonableness, and how these concepts are applied to clinical practice. We will then use two case studies to show that, while matters of definition may appear to be of limited importance to practicing physicians, these definitions can have profound consequences both for clinical practice and for health systems. In concluding, we will argue that there is unlikely to ever be a formal test to definitely determine whether a prescribing decision is justified and that physicians and the medical professions at large need to rediscover the concept of reasonableness.