The long-standing view that ketamine is simply an NMDA receptor antagonist has been progressively and fundamentally reshaped by a series of recent studies that have collectively redefined our understanding of how ketamine and its enantiomers act therapeutically but also why it produces reinforcement and has liability for misuse and addiction. Excited to share this News & Views (rdcu.be/fBIc8) written with @jorgh82 and published yesterday in @NatureSMB on the recent work of Qianru Jiang, Tao Che and colleagues who showed that ketamine (as well as PCP) can bind directly within the orthosteric pockets of both mu and kappa opioid receptors. The Jiang et al. findings, taken together with other recent studies support a bifunctional model in which NMDA and opioid receptor signaling may work together to shape ketamine's antidepressant, analgesic, dissociative, and reinforcing effects. Understanding how these systems converge could inform the development of next-generation treatments that preserve therapeutic benefits while reducing the risks of misuse and adverse effects.