The release of polypeptides in response to extracellular cues is a notable feature of endocrine, exocrine and neuronal cells, and is based on regulated exocytosis via dense-core secretory granules. There is interest in this mode of secretion because of its importance in human physiology and also because regulated exocytosis reflects a complex pathway of membrane traffic that includes compartment-specific reversible macromolecular assembly, coat-independent vesicle budding, maturation/remodeling of both lumenal and membrane constituents, and stimulus-dependent membrane fusion. Secretory granules are absent in most unicellular model organisms but are highly developed in the Ciliates, which therefore offer attractive systems to study these phenomena. In Tetrahymena thermophila, biochemical and genetic approaches have begun yielding insights into issues ranging from control of granule core assembly, based on reverse genetic analysis of granule cargo, to questions about factors involved in granule biogenesis, based on random mutational approaches.