Researchers, clinicians and statisticians involved in the design and conduct of a placebo-controlled clinical trial are painfully aware of the extent to which the magnitude of the placebo response in a study can determine the success of the study. Multiple factors affect the order of magnitude of the placebo response. Some of these may be minimized in the design of a trial. Others may at best be planned for. Some factors contributing to the placebo response are poor inclusion/exclusion criteria, poorly validated outcome measures, measurement error, poor quality of data entry and verification, regression toward the mean and natural history of the disease. Factors contributing to the placebo response with examples will be given, along with specific strategies for reducing the placebo response.