ARPP-16 and ARPP-19 are 2 cAMP-regulated phosphoproteins of Mr = 16,000 and 19,000, respectively, which are identical except for the presence of 15 additional amino acids on the NH2-terminus of ARPP-19. The phosphorylation of these 2 proteins is regulated by cAMP and vasoactive intestinal peptide in reaggregate striatal cultures (Girault et al., 1988). Using immunoblots and immunocytochemistry, we have compared the regional, subcellular, phylogenetic, and ontogenetic distributions of these 2 proteins. ARPP-19 was found in all vertebrate species studied and, at various levels, in all tissues of adult rat. ARPP-19 was also present at high levels in malignant cell lines. During development ARPP- 19 concentrations were highest in the embryo and decreased during the pre- and postnatal periods. In contrast, ARPP-16 was detected only in some specific neurons of the dopamine-innervated regions of the basal ganglia and the cerebral cortex, which are known to possess D1 dopamine receptors, in particular the striatonigral neurons. ARPP-16 is phylogenetically recent, being found only in birds and mammals, and appears late in ontogenesis, increasing during the postnatal period. These 2 proteins provide a unique model for studying the specificity of signal transduction and gene expression in dopaminoceptive neurons.