Research in end-of-life care is constrained more by pragmatic, social, cultural, and financial constraints than ethical issues that preclude the application of typical research methodologies. When normally accepted and ethically sound protections for subjects (especially for those who lack independent decision-making) are in place, exclusion of patients with far advanced disease from research is in and of itself unethical. Involvement in research may have a therapeutic, anticomiogenic effect on dying patients and their families. Institutional review boards must be educated to evaluate research protocols involving this group of vulnerable patients with an eye toward assuring that ethical safeguards are in place, conflicts of interest are transparent and minimized, and that the proposed methodology has duly considered all practical exigencies so that resources and peoples’ time and emotional investments are not squandered. Investigators and research review committees must be knowledgeable about placebo effects and under what types of circumstances their use is justifiable, preferred or requisite to fulfill both ethical and scientific imperatives. Examples of investigations using various research methodologies, along with their respective ethical considerations are provided.