This article reviews studies of the placebo response in antidepressant clinical trials, describes methods that have been attempted to decrease it, and discusses implications of the placebo response in depression for research on treatments for neuropathic pain. Literature reviews and research studies examining the placebo response in clinical trials of treatments for depression were reviewed. Existing data suggest that the placebo response in antidepressant clinical trials is substantial and that a high placebo response in a clinical trial is associated with a reduced likelihood of demonstrating the statistical superiority of antidepressant treatment vs. placebo. Attempts to decrease the placebo response in antidepressant clinical trials have generally not been effective. In addition, there is little evidence that decreasing the placebo response rate makes it more likely that superiority of active vs. placebo treatment will be demonstrated. Analyses of neuropathic pain clinical trial databases should be conducted to examine factors associated with trial outcomes. Aspects of neuropathic pain clinical trials that require further consideration or investigation include the following: (a) exclusion of patients with mild pain severity; (b) exclusion of patients with short episode duration; (c) maximizing reliability, validity, and responsiveness of outcome measures; (d) minimizing extraneous contact with investigative staff and other sources of nonspecific therapeutic effects; (e) trial duration; (f) minimizing the number of treatment groups; (g) flexible vs. fixed dose designs; (h) strategies for identifying patients and accelerating enrollment; (i) identification of run-in periods that reduce the placebo response rate; and (j) registration of clinical trials and publication of negative studies.