Romantic rejection is tied to a deep experience of loss and negative mood, with the potential to precipitate clinical depression and, in extreme cases, fatal outcomes. To begin mapping the brain systems that underlie this natural state of loss, the study used functional brain imaging to examine 15 individuals (10 women and 5 men) who had recently been rejected by a partner yet remained intensely attached. During sessions, participants alternated between viewing a photo of the person who had rejected them and a photo of a familiar, unrelated individual, while also performing a distracting task. When looking at the rejected partner, participants reported experiencing love, despair, memories that were positive or negative, and reflections on why the rejection occurred. Brain activity showed that viewing the beloved activated regions involved with processing rewards and losses, craving, and the regulation of emotion. The activation encompassed the ventral tegmental area on both sides, the ventral striatum, portions of the orbitofrontal/prefrontal cortex, and the cingulate gyrus. When these neural responses were compared with data from individuals who were happily in love, the pattern pointed to engagement of mesolimbic reward and survival circuits in romantic passion regardless of whether the relationship was characterized by happiness or distress. Additionally, higher-order forebrain areas related to motivational significance, gain and loss, experiences akin to cocaine craving or addiction, and emotion regulation emerged as active players, suggesting that learning and prior experience may shape how rejection reactions are processed in the brain. These findings indicate that reward networks, previously highlighted in studies using monetary incentives, become engaged in a natural, internally driven negative emotional state. The involvement of regions associated with addictive processes offers a possible explanation for the obsessive behaviors sometimes observed during heartbreak, indicating that similar neural substrates underlie both intense romantic fixation and craving-like states. Overall, the results illustrate how the brain recruits both primary reward systems and more complex, experience-weighted circuits to process the pain and preoccupation that accompany romantic rejection.