Clinical trials are interventional studies that investigate specific health questions in human participants, often studying an investigational treatment in a specific patient population. In 2019, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) released the E9(R1) guideline for precisely describing treatment effects corresponding to clinical questions of interest in clinical trials. Before the release of the ICH E9(R1) guideline, treatment effects were often ambiguously defined, and descriptions of the clinical questions of interest were usually missing in the protocol, potentially leading to problems with the interpretation of the reported treatment effects. In this introductory chapter, we provide a clinical trial example where the absence of an agreed definition of treatment effect (or estimand, i.e., “what is to be estimated”) led to a disagreement between the sponsor and the regulator regarding the clinical question of interest, which impacted the approvability of the drug. Motivated by examples like this, the ICH E9(R1) guideline proposed a structured framework to strengthen the dialogue between disciplines involved in the formulation of clinical trial objectives, design, conduct, analysis, and interpretation, as well as between the sponsor and the regulator regarding the treatment effect(s) of interest that a clinical trial should address. The use of a structed framework formalizes the entire thinking process and communication among different stakeholders. By adopting it, the dilemma in the motivating example could have been avoided.