1. Enkephalinergic cells are found throughout the diffuse neuroendocrine system, in the adrenal medulla, brain, spinal cord, peripheral and enteric nervous systems, and endocrine pancreas. 2. In each of these diverse cell types, the enkephalin phenotype is (i) established during development, (ii) modified by the particular environment in which the cell is located, and (iii) maintained by ongoing biosynthesis at a rate consistent with loss of enkephalins from the cell during periods of secretion. 3. Enkephalin expression and biosynthesis have been studied in several neuroendocrine cell types and tumor cell lines. Transcriptional, translational, and posttranslational factors can play a role at all three stages (establishment, modification, and maintenance) in the regulation of enkephalin expression during the lifetime of the cell. 4. Cyclic nucleotides, glucocorticoids, and calcium may all act to control the overall level of enkephalin biosynthesis pretranslationally, while regulation of posttranslational processing of proenkephalin seems to be important in determining the pattern of proenkephalin-derived opiate peptides produced in a given tissue. 5. The themes (and variations) of cell regulation that apply to enkephalin expression may be similar for other bioactive peptides produced in neural and endocrine tissues.