Although the neural underpinnings of music cognition have been widely studied in the last 5 years, relatively little is known about the neuroscience underlying emotional reactions that music induces in listeners. Many people spend a significant amount of time listening to music, and its emotional power is assumed but not well understood. Here, we use functional and effective connectivity analyses to show for the first time that listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the nucleus accumbens (NAc) and the ventral tegmental area (VTA), as well as the hypothalamus and insula, which are thought to be involved in regulating autonomic and physiological responses to rewarding and emotional stimuli. Responses in the NAc and the VTA were strongly correlated pointing to an association between dopamine release and NAc response to music. Responses in the NAc and the hypothalamus were also strongly correlated across subjects, suggesting a mechanism by which listening to pleasant music evokes physiological reactions. Effective connectivity confirmed these findings, and showed significant VTA-mediated interaction of the NAc with the hypothalamus, insula, and orbitofrontal cortex. The enhanced functional and effective connectivity between brain regions mediating reward, autonomic, and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences.