The intracellular sorting of peptide hormone precursors to the dense core secretory granules (DCSGs) is essential for their bioactivation. Despite the fundamental importance of this cellular process, the nature of the sorting signals for entry of proteins into DCSGs remains a source of vigorous debate. This review highlights recent discoveries that are consistent with a model in which several protein domains, acting in a cell-specific fashion and at different steps in the sorting process, act in concert to regulate the entry of proteins into DCSGs.