Nociceptive circuitry processes the signals evoked by activating specialized peripheral sensory receptors for pain perception. Recent studies show that the neuronal phenotypes in the dorsal root ganglia and spinal dorsal horn are determined by distinct sets of transcription factors during development. Anatomical analyses with genetic approaches demonstrate that each subset of nociceptive sensory neurons has topographically distinct circuits at both spinal and brain levels. Moreover, the sensitivity of primary afferents can be rapidly regulated not only by phosphorylation of receptors, ion channels and associated regulatory proteins but also by stimulus-induced cell surface expression of G-protein-coupled receptors. In chronic pain states the molecular characteristics of spinal nociceptive circuits are altered, enabling normal peripheral stimuli to induce pain hypersensitivity.