Current and coincident biomedical advances make this an opportune time to encourage research with individuals who have fluctuating periods of incapacity caused by psychotic disorders like schizophrenia. Effecting research with this heterogeneous population who may have impaired decision-making capacity that diminishes their autonomy, while honoring their liberty and safeguarding their well-being, may be difficult to achieve. Federal regulations and guidelines in regard to research with this population are insufficient and cause additional obstacles. Use of research advance directives that allow for the appointment of a surrogate decision maker, the designation of a research monitor, and delineation of specific safeguards for the research participants also may provide protection for investigators and foster and improve community trust in medical research.