ClinicalTrials.gov, a repository of information about clinical studies and their results, together with specialised search tools, provides a unique window into the clinical research enterprise, which includes all initiated, ongoing, and completed or terminated clinical studies. Researchers are increasingly using information from the database to assess research reporting practices, or to characterise the clinical research enterprise. Conducting valid analyses requires an understanding of both the capabilities and limitations of the database (that is, intrinsic factors) as well as reporting policies and other factors external to the database that influence the types of studies in ClinicalTrials.gov in a specified time. This article discusses 10 key issues that researchers need to consider when using the database to conduct research.