This fifth article in a seven part series presents the Core GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to systematic reviews, clinical practice guidelines, and health technology assessments and addresses issues of indirect evidence. Guideline developers and health technology assessment practitioners must carefully specify the population, intervention, comparison, and outcome (PICO)—their target PICO—and consider the extent to which the best available evidence matches their target. When target and study PICOs differ substantially, studies provide indirect evidence and Core GRADE users may rate down the certainty of evidence as a result of this indirectness. Whether examining studies from a search for direct evidence or a deliberate search for indirect evidence, for each substantial difference between target and study PICO, Core GRADE users must judge the likelihood that magnitude of effects will differ substantially. The greater the likelihood of substantial differences the more advisable rating down for indirectness.