Systematic reviews and clinical practice guidelines are useful tools for bringing evidence into pain practice. However, even when their conclusions or recommendations appear valid, interpreting and applying systematic reviews and clinical practice guidelines in everyday practice is not always straightforward. Judging external validity or applicability of findings requires careful consideration of factors related to patient selection, clinical setting, feasibility, costs, and availability of interventions. Clinicians should also consider whether effects on clinically relevant outcomes are large enough to warrant use of the intervention in question. Other challenges to using systematic reviews and clinical practice guidelines in pain practice include the need to make decisions about pain interventions when evidence is weak or inconclusive, and the increasing and confusing presence of discordant systematic reviews and clinical practice guidelines. This article discusses how to evaluate applicability and clinical relevance of systematic reviews and clinical practice guidelines, and provides a framework for approaching clinical decisions when evidence is weak or conflicting.