Researchers face challenges in balancing the demands of sound research methods and ethical standards in studies involving persons with mental retardation. While the autonomy of individuals must be respected, researchers also have an ethical responsibility to protect vulnerable individuals from social, psychological, or physical risks of research participation. Some individuals may face significant barriers in the research decision-making process due to cognitive limitations, lack of information and support, and limited experience and opportunities for exercising choice. The historical context of biomedical and behavioral research involving persons with mental retardation and current ethical issues related to informed consent and surrogate decision-making are examined. Implications for researchers and professionals are discussed, including ways to support individuals with mental retardation and their families in research decision-making.