In recent years, placebo becomes an important issue in evidence-based research. Basic sciences started elucidating the neurobiological and psychological processes that mediate the placebo response. A placebo effect is affected by the variation of illness, such as the natural course of disease. Patient or physician bias can also cause misinterpretation of the placebo effect. In research, the placebo effect is therapeutic noise to be removed by placebo-controlled trials. Thus, a randomized, double-blind, placebo-controlled trial has emerged as the gold standard in modern clinical study. The purpose of this article was to discuss the issue related to placebo, placebo effects, placebo mechanism, ethics of using placebos, and methodology referring to intervention research design of the clinical research in nursing.