Our knowledge of prohormone and proneuropeptide processing and its relationship to the secretory pathway has advanced significantly in the last five years. The recent discovery of the prohormone convertase family of proteolytic enzymes has provided new candidates for the prohormone and proneuropeptide convertases. The increasing appreciation of the role of proteolysis in diverse cellular processes has also brought the prohormone processing field closer to the fields of growth factor processing, the role of host proteases in viral and bacterial pathogenesis and toxicity, control of the cell cycle, inflammation, and apoptosis. The last five years have been very productive, but the most interesting questions are still unanswered. Which enzymes are actually responsible for prohormone cleavages in specific tissues? What structural features of the prohormones determine where it will be processed or how it is recognized as secretory material by the sorting machinery? How is tissue-specific processing determined and regulated? The availability of protease knockout mice and and a more detailed understanding of the complex biosynthetic activation of these enzymes will provide at least some of the answers.