Placebo (PL) treatment is a method utilized as a control condition in clinical trials. A positive placebo response is seen in up to 50% of patients with Parkinson disease (PD), pain syndromes, and depression. The response is more pronounced with invasive procedures or advanced disease. Physiologic and biochemical changes have been studied in an effort to understand the mechanisms underlying placebo-related clinical improvement. In PD, objective clinical improvements in parkinsonism correlate with dopaminergic activation of the striatum, documented by PET and with changes in cell firings of the subthalamic nucleus documented by single cell recordings. Dopaminergic pathways mediating reward may underlie PL-mediated improvement in PD. In pain syndromes, endogenous opioid release triggered by cortical activation, especially the rostral anterior cingulated cortex, is associated with PL-related analgesia and can be reversed by opioid antagonists. Covert treatment of an analgesic is less effective than overt treatment, suggesting an expectation component to clinical response. In depression, PL partially imitates selective serotonin reuptake inhibitor-mediated brain activation. Diseases lacking major "top-down" or cortically based regulation may be less prone to PL-related improvement.