Endogenous opioid and non-opioid mechanisms (for example, dopamine (DA), endocannabinoids (eCB)) have been implicated in the formation of placebo analgesic effects, with initial reports dating back three decades. Besides the perspective that placebo effects confound randomized clinical trials, the information so far acquired points to neurobiological systems that when activated by positive expectations and maintained through conditioning and reward learning are capable of inducing physiological changes that lead to the experience of analgesia and improvements in emotional state. Molecular neuroimaging techniques with positron emission tomography and the selective μ-opioid and D2/3 radiotracers [11C]carfentanil and [11C]raclopride have significantly contributed to our understanding of the neurobiological systems involved in the formation of placebo effects. This line of research has described neural and neurotransmitter networks implicated in placebo responses and provided the technical tools to examine inter-individual differences in the function of placebo-responsive mechanisms, and potential surrogates (biomarkers). As a consequence, the formation of biological placebo effects is now being linked to the concept of resiliency mechanisms, partially determined by genetic factors, and uncovered by the cognitive emotional integration of the expectations created by the therapeutic environment and its maintenance through learning mechanisms. Further work needs to extend this research into clinical conditions where the rates of placebo responses are high and its neurobiological mechanisms have been largely unexplored (for example, mood and anxiety disorders, persistent pain syndromes or even Parkinson disease and multiple sclerosis). The delineation of these processes within and across diseases would point to biological targets that have not been contemplated in traditional drug development.Molecular Psychiatry advance online publication, 16 December 2014; doi:10.1038/mp.2014.164.