Whole-genome/exome sequencing used in clinical trials (CTs) to identify 'druggable' mutations and targets uncovers incidental findings unrelated to the trial objectives but of value for participants, although ethically challenging. To be disclosed to trial participants, the analytical validity, clinical validity, clinical utility, clinical relevance and actionability of incidental genomic findings (IGFs) must be established. Special considerations should be taken with minors to disclose only those findings related to early-onset conditions or diseases and in cases where early implementation of measures is necessary to prevent the occurrence of diseases. A plan for disclosing incidental findings that classifies the types that can be found, and who, when and how these findings will be disclosed to participants, should be included in the trial protocol to be approved by the relevant institutional review board. IGFs in CTs raise new ethical challenges that must be discussed by CT stakeholders, professional associations and patient advocates.