Neurons in the superficial dorsal horn (SDH) of the spinal cord play a critical role in processing potentially painful or noxious signals from skin, muscle, and viscera. Many acute pain therapies are based on the notion that altering the excitability of SDH neurons can block or gate these signals and reduce pain. This same notion also underlies treatments for certain chronic pain states. Basic scientists are now beginning to identify a number of potential molecular targets for spinal cord–based pain therapies with a focus on ion channels and receptors that can alter neuronal excitability. The current challenge in pain research is to identify which are the most promising targets and how their manipulation alters pain processing. In this review, we propose that our understanding of spinal pain processing mechanisms and translation of these discoveries into pain therapies could be improved by 1) better appreciating and understanding neuronal heterogeneity in the SDH; 2) establishing connectivity patterns among SDH neuron types; and 3) testing and extending findings made in vitro to intact (in vivo) animal models. As this information becomes available, it will be possible to determine the precise distribution of potential therapeutic targets on various SDH neuron types within specific circuits known to be functionally important in spinal pain processing.