The practice of evidence-based medicine (EBM) begins with the formulation of a clinical question. Clinical questions consist of three parts: the patient or population, the interventions to be compared and the clinically relevant outcomes. This chapter describes a strategy for formulating answerable clinical questions. The formulation of the clinical question is the starting point; whether you intend to use EBM in the handling of an individual patient, if you are writing a clinical guideline for the department you work in, or you are preparing a systematic review. When performing a systematic review, the approach could be to include a wide group of patients and if plausible, plan some subgroup analysis in advance if there is a suspicion that some groups will be different from the others. Spending time and energy, formulating the clinical question before undertaking the literature search, and appraisal, are likely to improve the outcome of the process.