Research during the past decade has revealed the existence of neural systems that modulate pain transmission. Much of this work has focused on the role of endogenous opiate systems, but recent research indicates the involvement of nonopiate mechanisms as well. In this article, we present data demonstrating that opiate and nonopiate analgesia systems can be selectively activated by different environmental manipulations and describe the neural circuitry involved. Both neural and hormonal pathways and both opiate and nonopiate substances play roles in the complex modulation of pain transmission. The existence and description of these modulatory mechanisms have important clinical implications for the treatment of pain.