Opponent-Process Theory (OPT) provides a framework for understanding the neurobiological and behavioral dynamics of addiction. First introduced by Solomon and Corbit in the 1970s, OPT posits that a drug’s positive effects (the “A-process”) are automatically countered by an opposing negative effect (the “B-process”) that strengthens with repeated use (Solomon and Corbit, Psychol Rev 81:119–145, 1974). With time, acute euphoria yields to tolerance and increasingly severe withdrawal, shifting motivation from seeking pleasure to avoiding pain. This chapter examines the neuroadaptations underlying OPT in substance use disorders, including how tolerance and withdrawal develop and how reinforcement transitions from positive to negative. Key changes in brain reward and stress systems (e.g., dopamine downregulation, recruitment of stress neurotransmitters) drive an allostatic “hedonic contrast” resulting in a lowered reward baseline coupled with heightened stress sensitivity. These opponent-process adaptations help explain the persistence of addiction and its resistance to cessation, and they inform modern strategies for treatment and relapse prevention.