Key elements in guiding the design choice of randomized clinical trials (RCTs) are the research question, the related hypothesis and appropriate methodology, ethics, feasibility, quality of evidence, and efficiency. The strength of RCTs is their internal validity, allowing for causal inference by attributing the observed outcomes to the type of treatment(s) and allowing the randomization to otherwise balance the study groups, thus addressing known and unknown potential confounders.¹ RCTs offer high-quality evidence but are not always ethical, feasible, or necessary. If an RCT is feasible and possible,² a choice has to be made between several options. The involvement of methodological and statistical experts will ensure success in the selection and implementation of the best design. In this article, we present the strengths and weaknesses of several RCT design options (Box).