Typically, protection of human subjects is a shared responsibility involving the local institutional review board (IRB) and the clinical investigator, guided by federal and state law as well as local organizational policy. The IRB screens protocols to ensure subjects' safety by making sure that risks are acceptable and do not outweigh benefits. However, the recruitment of subjects, as well as obtaining consent, is the principal investigator's responsibility. Through the process of informed consent, the clinical investigator is obliged to ensure that each subject understands all treatments proposed and their potential benefits and risks. Achieving truly informed consent from people with major developmental, physical, sensory, communicative, or cognitive disabilities may be particularly difficult. Spurred on by increasing research of relevance to rehabilitation medicine and the patients served, we review legal, ethical, and moral issues surrounding the processes of obtaining informed consent and offer specific recommendations for protecting people with disabilities.