Reports of genomic sequencing being applied to the medical care of individual patients have begun to appear in the scientific literature, but much needs to be done before the use of sequence data will be routine. It is unclear what diseases or individual susceptibilities will be usefully addressed by a genomic sequencing approach, or the potential range of clinical applications. Furthermore, incorporation of comprehensive genomic sequence data into clinical care will require changes to institutional policies, standard procedures (including simplified analysis and interpretive tools), and the ability to integrate sequence information into the clinical workflow. The ethical and psychosocial implications of returning genomic variation data, with all of the caveats regarding statistical uncertainties and incomplete knowledge, remain poorly understood. NHGRI has initiated a Clinical Sequencing Exploratory Research program intended to support both the methods development needed to integrate sequencing into the clinic and the ethical and psychosocial research required to responsibly apply personal genomic sequence data to medical care. The program will also provide a forum for the development and dissemination of innovative and best practices in this area. The Clinical Sequencing Exploratory Research program supports multi-disciplinary projects that bring together clinicians, bioinformaticians, and ethicists to research the challenges of utilizing genomic sequence data in the clinic in the routine practice of medicine. The challenges are many and not disease-specific. Important aims of the research include: development of technical specifications and standards for sequencing in a clinical setting, investigation of methods to transmit genome-scale data to physicians in a fashion and timescale that fits the normal clinical workflow, exploration of regulatory requirements for applying genomic sequence data to patient care, and study of the ethical implications of returning unintended findings. A U01 cooperative agreement mechanism is being used to promote the development of a robust forum for debate of issues, practical and philosophical. Also, the consortium of grantees will cooperate to evaluate best practices in this rapidly advancing field and communicate these to the community.