There is probably no other human phenomenon that better reflects the inseparable interaction between psychological and somatic factors than the placebo effect. This phenomenon is a complex psychobiological process consisting of learning and expectancy components acting on neurophysiological systems, and its efficacy has been confirmed empirically in a range of fields such as pain and the immune system. Inert substances such as sugar pills can trigger placebo effects, and these effects can also enhance the response to active treatments. This topical issue presents the complexity of the phenomenon called placebo effect. The articles included here describe different research approaches to the topic and look at different models and facets of the placebo phenomenon. During the past decades the most impressive demonstrations of these effects have been presented in the field of pain and placebo analgesia. The effectiveness of analgesic placebo responses remains unchallenged and our knowledge about the underlying mechanisms that produce the placebo effect is expanding rapidly. Together with expectancy theories, classical conditioning has been discussed as being a major explanatory model. However, other learning principles, such as social learning (via vicarious reinforcement), are thought to play an important role in the development and maintenance of placebo analgesia. From a neurobiological viewpoint, research findings have revealed the involvement of cortical, subcortical, and recently spinal structures in the placebo-induced modulation of pain that cognitively triggers the release of endogenous opioid and non-opioid substances (Colloca, Klinger, Flor, & Bingel, 2013). Insights into the underlying mechanisms and the neurobiological foundation (Colloca et al., 2013) of the analgesic placebo effect have now made it possible to develop principles for clinical application (Klinger, Colloca, Bingel, & Flor, 2014). These principles must, of course, be justifiable within ethical boundaries. In their article addressing this issue, Colloca, Jonas, Killen, Miller, and Shurtleff (2014) point out that, in the current state of medicine, there are numerous examples of inappropriate uses of placebos, often justified by the patient’s urgency for help on the one hand, and the lack of appropriate medication on the other. The authors emphasize the need to focus on elements of the clinical encounter and the patient-physician relationship to increase the placebo effect. Clearly caution is necessary in harnessing placebo effects in medicine to treat patients while avoiding deception. Accordingly, the study of the placebo effect should be incorporated in the core clinical practice curriculum of all health practitioners. Benedetti, Amanzio, and Maggi (1995) and Colloca, Lopiano, Lanotte, and Benedetti (2004) showed that pain treatments (e.g., opioids) consist of a verum component (active pharmacological component) and a placebo component. Regarding the latter, there are many contextual factors associated with the treatment, such as expectancy, fear, previous experiences with clinical staff, and co-interventions, but also illness-related factors and personality variables. It is necessary to boost these specific aspects systematically to ultimately enhance the analgesic effect. In Germany, for instance, this innovative thought has already been implemented in the S3 guidelines of the working group of scientific medical societies (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF – see http://www.awmf.org); this association represents Germany in the Council for International Organizations of Medical Sciences, CIOMS) for the ‘‘treatment