Based on the observation that the placebo effect in Parkinson's disease was mediated by the release of endogenous dopamine in both the dorsal and ventral striatum, in 2002 we formally proposed the placebo-reward hypothesis. This hypothesis establishes a link between the placebo effect and reward mechanisms, and predicts that the activation of the ventral striatum should be present in any placebo response, in any medical condition. In keeping with this prediction, functional neuroimaging studies have shown placebo-induced activation of the reward circuitry in Parkinson's disease, depression, and pain. In fact, recent evidence suggests that the release of dopamine in the ventral striatum likely triggers the activation of the endogenous opioid system in placebo analgesia. The placebo-reward hypothesis also supports the notion that the expectation of clinical benefit plays a major role in the placebo effect. Probability and trust, two key factors involved in shaping expectations, must therefore be essential to the development of placebo responses. The ventral loop of the basal ganglia circuitry (anterior cingulate cortex-ventral striatum-ventral pallidum- mediodorsal nucleus of the thalamus -anterior cingulate cortex) is a fundamental component of the neuroanatomy of the placebo effect.