Sympathetic neurons and chromaffin cells derive from common sympathoadrenal precursors which arise from the neural crest. Cells from this lineage migrate to their final destination and differentiate by acquiring a catecholaminergic phenotype in response to different environmental factors. It has been shown that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its PAC1 receptor are expressed at early stages of sympathetic development, and participate to the control of neuroblast proliferation and differentiation. PACAP also acts as a neurotransmitter to stimulate catecholamine and neuropeptide biosynthesis and release from sympathetic neurons and chromaffin cells, during development and in adulthood. In addition, PACAP and its receptors have been described in neuroblastoma and pheochromocytoma, and the neuropeptide regulates the differentiation and activity of sympathoadrenal-derived tumoral cell lines, suggestive of an important role in the pathophysiology of the sympathoadrenal lineage. Transcriptome studies uncovered genes and pathways of known and unknown roles that underlie the effects of PACAP in the sympathoadrenal system.