The nature and determinants of the placebo response are widely unknown and are discussed controversially. This review presents a unifying concept for the understanding of the placebo response in clinical trials and practice based on three components: "Regression to the mean", "Pavlovian conditioning", and "Signal detection theory", and discusses the respective literature in light of experimental and clinical findings from psychology, psychiatry, neurology, and gastroenterology, with specific emphasis on "brain imaging" of the placebo response.