OBJECTIVES: In developing new medicines, pharmaceutical companies face the complex and challenging task of choosing comparators, in the absence of clear and consistent guidance, in order to produce evidence that best meets diverse stakeholder needs. This lack of clear and consistent guidance has led to several high-profile cases in which HTA bodies rejected products receiving regulatory approval due to a lack of evidence relative to desired comparators. Our objective was to identify key issues in comparator selection and present case studies highlighting these issues. METHODS: We conducted a comprehensive search of the published and grey literature addressing comparator selection, including formal guidelines from major regulatory, HTA, and professional organizations, as well as case studies and published opinions. Three authors independently and qualitatively assessed the identified literature, and the final list of issues was agreed upon through team discussion and consensus. RESULTS: Key challenges in the selection of appropriate comparators include: 1) lack of a standard definition for “standard of care,” 2) concerns regarding off-label usage; 3) changes in requirements due to market dynamics; and 4) RCT design issues. We explore several of these challenges further with case studies. CONCLUSIONS: Due to challenges inherent in meeting diverse stakeholder needs, the selection of comparators is a complex and multi-faceted problem. The challenges we identified highlight the need for more uniformity and clarity among existing standards. In the context of ongoing external standard setting and harmonization efforts, organizations seeking to provide guidance around comparator selection should consider the issues described herein and work towards the common goal of a more transparent, harmonized process that optimizes the production of evidence that best meets the needs of all stakeholders.