For as long as the federal regulations governing human subjects research have existed, the practice of informed consent has been attacked as culturally biased, legalistic, ritualistic and unevenly enforced. Its focus on meeting the regulatory requirements is seen as undermining a truly ethical process that produces informed and voluntary participation in medical research. Recent changes in the clinical translational research enterprise, with large scale genomic and other data sharing made possible by advanced bioinformatic technologies, may further challenge this goal. Study participants are asked to consent to future studies with unspecified aims, broad data sharing policies and ongoing uncertainties regarding confidentiality protections and the potential benefit of incidental genomic research findings. Because more research is conducted under these new conditions, the very nature of the researcher-subject relationship is shifting and will require new governance mechanisms to promote the original goals of informed consent.