Background: With the use of next generation sequencing technologies, translational research is becoming a catalyst for the implementation of personalized medicine (PM). To implement PM, we will also need to ensure that sensitive results are shared, used and returned to the participants in compliance with applicable ethical and legal frameworks. Furthermore, the increasingly blurred distinction between research and clinical practice in this context will require improving governance processes to better protect the rights and interests of research participants. In response to this challenge, innovative solutions are emerging in the literature, including that of a “trusted third party” or “gatekeeper”.Objective: Our research seeks to explore the multiple roles that such a gatekeeper could undertake in the context of PM and to implement some of these roles in a customized gatekeeper framework. Method: The research consists of a comparative analysis of the governance frameworks of selected large-scale PM projects. A gatekeeper framework, namely the DataTrust, is presented to provide a prototype for other research projects to use or build on. Results: Possible oversight functions, roles and responsibilities of a gatekeeper are identified leading to the development of the DataTrust. Such functions, roles and responsibilities may include, but are not limited to: protecting the integrity of the consent process; safeguarding data confidentiality; reviewing access requests from members of the scientific community; and ensuring overall ethics compliance and oversight for the return of results. Conclusion: We propose that the integration of a gatekeeper, with specific functions tailored to each project, could enhance compliance with applicable ethical and legal standards and protect the rights and interests of research participants.