Placebos and placebo effects have held an ambivalent place in health care for at least two centuries. On the one hand, placebos are traditionally used as controls in clinical trials to correct for biases. Among other factors, these include regression to the mean, the natural course of the disorder, and effective co-interventions. In this context, the placebo effect is viewed as an effect to be factored out in order to isolate and accurately measure the specific effects of the treatment. On the other hand, there is mounting scientific evidence that placebo responses represent complex psychoneurobiological events involving the contribution of the distinct central nervous system as well as peripheral physiological mechanisms that influence pain perception, clinical symptoms, and substantially modulate the response to active analgesics. In this review, we bring together three perspectives of placebo research including psychological mechanisms, neurobiological pathways and molecular substrates of placebo analgesia and their contribution to active pain medications. The emphasis is particularly on recent studies illuminating mechanisms underlying individual differences in placebo responsiveness.