Neuroendocrine cells respond to hormones and synaptic input by increasing or decreasing their own electrical activity and secretory output, and by changes in the repertoire of expression of neuronal genes. Neuropeptide genes are among those whose transcription rates can be dramatically up-and downregulated when neuronal activity is altered. In the last decade or so, our understanding of neuropeptide gene regulation has evolved from the concept of calcium-dependent coupling of neuropeptide secretion and biosynthesis to the current perspective of neuropeptide genes as the targets of multiple intracellular signaling pathways, entrained by intrinsic electrical activity and by transsynaptic influences. This review describes our current understanding of neuropeptide gene regulation in the adrenal gland as well as in the peripheral and central nervous systems. Particular emphasis is placed on the molecular mechanisms that allow unique patterns of expression of neuropeptide genes within specific types of neuroendocrine cells that contribute to the remarkable anatomical specificity of neuropeptide gene expression.