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The approach adopted is exemplified using two prominent clinical problems, namely (a) the \u2018reversible\u2019 versus \u2018irreversible\u2019 pulpitis conundrum and (b) persistent idiopathic dentoalveolar pain (PIDAP). Pulpitis under deep caries or dentinal cracks is understood from a histological perspective, but clinical assessment tools to indicate irreversibly inflamed aspects of the dental pulp are elusive. PIDAP, on the other hand, is a diagnosis of exclusion; its pathophysiology is complex and not understood sufficiently to avoid unnecessary dental treatments. This review addresses how diagnostic biomarkers could further our understanding of those and other clinical problems, and how issues can be tackled from a methodological point of view. Hence, different methodological approaches to identify suitable diagnostic biomarker(s) or use known biomarkers are presented. The importance of asking a relevant research question, collecting the most suitable fluid and using the ideal collection vehicle for the research question under investigation is discussed based on the defined clinical problems.<\/jats:p>","DOI":"10.1111\/iej.13647","type":"journal-article","created":{"date-parts":[[2021,10,16]],"date-time":"2021-10-16T16:46:46Z","timestamp":1634402806000},"page":"37-45","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["A critical analysis of research methods to study clinical molecular biomarkers in Endodontic research"],"prefix":"10.1111","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9545-7828","authenticated-orcid":false,"given":"Matthias","family":"Zehnder","sequence":"first","affiliation":[{"name":"Clinic of Conservative and Preventive Dentistry University of Z\u00fcrich Center of Dental Medicine Z\u00fcrich 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