<b><i>Background:</i></b> Assessing the quality of clinical research is a key evidence-based practice skill. Clinicians, guideline producers, policy makers, service commissioners, and families need to have a sense of the validity, applicability, and certainty of research evidence when determining how it should inform their decision-making and practice. <b><i>Methods:</i></b> We consider the various methodological and study design factors that contribute to the validity and applicability of clinical research findings. We describe the “Grading of Recommendations Assessment, Development and Evaluation” (GRADE) methodology and discuss how this approach is used to assess and report certainty of evidence and strength of recommendations. <b><i>Results:</i></b> The randomized controlled trial (RCT) is the gold standard method for assessing interventions because randomization balances prognostic characteristics between comparison groups. The GRADE approach considers evidence from RCTs as high quality, but acknowledges that the quality and level of certainty of trial evidence may be “downgraded” based on consideration of threats across 5 domains: risk of bias in included trials, inconsistency between trials in outcome estimates, indirectness of the evidence, imprecision of estimates, and likelihood of publication bias. <b><i>Conclusions:</i></b> Structured critical appraisal using GRADE methods to assess risk of bias and other threats to the internal and external validity of RCTs and systematic reviews and meta-analyses of their data facilitates transparency and consistency in using evidence to inform policy and practice.