Many activities concerning the unknown involve the potential for risk, and clinical research is no exception. Some research participants experience correlative benefit; others do not. When the participants are adults, as in Phase I trials with healthy volunteers, we rely on a highly individualistic decision-making process based on autonomous choice. This assumes that the ability to make voluntary, competent, informed choices, evaluating the risks and benefits from a personal perspective, offers the best protection for research participants. Rightly or wrongly, we depend heavily on informed consent for protection. We have further refined our post-Nuremberg ethical principles by requiring that safety and toxicity of drugs and devices be first assessed on the least vulnerable. In addition, we assume Institutional Review Boards (IRBs) will screen out protocols involving an inappropriate level of risk.