<p>The medial prefrontal cortex (mPFC) serves as a critical hub in addiction pathology across binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation/craving stages. This review provides the roles of the mPFC in different stages of addiction, and a focus on the mPFC neurotransmitter systems, neural circuits, molecules and synaptic adaptations on the regulation of addictive behaviors. Neurotransmitter systems of dopaminergic, glutamatergic, and GABAergic imbalances are related to pathological addiction. Circuits of dynamic dysregulation in the mPFC interaction with the striatum, nucleus accumbens (NAc), ventral tegmental area (VTA), dorsal raphe nucleus (DRN), and amygdala drive stage-specific behaviors, such as the prelimbic cortex (PL)→NAc core promoting cocaine-seeking, the infralimbic cortex (IL)→NAc shell suppressing relapse. Alterations in excitation-inhibition of microcircuits pyramidal neurons, GABAergic interneurons impair top-down regulation. Synaptic plasticity induced by drugs is involved in pathological stage-specific addiction, such as persistent craving and compulsive behaviors. Targeting the mPFC circuits offers promising therapeutic strategies for addiction intervention.</p>