Integral membrane proteins of neuroendocine dense‐core vesicles (DCV) appear to undergo multiple rounds of exocytosis; however, their trafficking and site of incorporation into nascent DCVs is unclear. Previous studies with phogrin (IA‐2β) identified sorting signals in the luminal domain that is cleaved post‐translationally; we now describe an independent DCV targeting motif in the cytosolic domain that may function at the level of endocytosis and recycling. Pulse‐chase radiolabeling and cell surface biotinylation experiments in the pituitary corticotroph cell line AtT20 showed that the mature 60/65 kDa form that resides in the DCV is generated by limited proteolysis in a post‐trans Golgi network compartment with similar kinetics to the formation of the principal cargo, ACTH. Phogrin is exposed on the cell surface in response to stimuli and progressively internalized to a perinuclear compartment that overlaps with recycling endosomes marked by transferrin. Chimeric molecules of phogrin transmembrane and cytosolic sequences with the interleukin‐2 receptor α chain (Tac) were sorted to DCVs through the action of an extended tyrosine‐based motif Y654QELCRQRMA located in a 27aa sequence adjacent to the membrane‐spanning domain. A 36aa domain terminating in this sequence conferred DCV localization to Tac in the absence of any other cytosolic or luminal phogrin components. The endocytosis and DCV targeting of phogrin Y654 > A mutants correlated with the impaired binding of the phogrin cytosolic tail to the µ‐subunit of the AP2 adaptor complex in vitro.