Background: While there is some consensus on methods for investigating statistical and methodological heterogeneity, little attention has been paid to clinical aspects of heterogeneity. Objective: To present a critical overview of suggested methods for investigating clinical heterogeneity in systematic reviews (Part 1) and to compare this to methods in a sample of Cochrane reviews (Part 2). Methods: Part 1: We included resources providing suggestions for investigating clinical heterogeneity between controlled clinical trials included in systematic reviews. We searched databases (Medline, EMBASE, CINAHL, Cochrane Library, CONSORT database), reference lists, and contacted experts. We extracted recommendations, assessed resources for risk of bias (ROB), and collated the recommendations. Part 2: We included the 100 most recent Cochrane Reviews, extracted thier methods of investigating clinical heterogeneity and compared this to findings from part 1. Results: We included 84 resources including narrative reviews, methodological reviews, statistical methods papers, and text books. These resources generally had a low ROB and there was minimal consensus among them. Resources suggested that planned investigations of clinical heterogeneity should be made explicit in the protocol of the review, clinical experts be included on the review team, that a set of clinical covariates should be chosen (Consider variables from the participant level, intervention level, outcome level, research setting, or others unique to the research question), that have a clear scientific rationale. Cochrane reviews under report methods for investigating clinical heterogeneity and do not follow current recomendations. Discussion: Formal recommendations are required for investigating clinical heterogeneity in systematic reviews of controlled trials.