Secretory granules are the cellular organelles mediating storage and regulated secretion of proteins. Their biogenesis involves sorting of secretory protein cargo and membrane constituents, which takes place at two distinct levels, the trans-Golgi network and the immature secretory granule. At both levels, sorting is accomplished by cargo aggregation and cargo-membrane recognition. Given not only the aggregative properties of the regulated secretory proteins but also the ability of lipids to form distinct membrane microdomains, self-organization of both lumenal and membrane constituents is proposed to play a crucial role in secretory granule biogenesis.