Human eosinophils contain within their cytoplasmic granules multiple preformed proteins, including over three dozen cytokines with nominal Th1, Th2 and immunoregulatory capabilities, and four distinctive cationic proteins. The secretion of these granule-derived proteins within eosinophils occurs principally by a mechanism whereby selected proteins are mobilized into vesicles for transport to and release at the cell surface. In contrast, the enigmatic presence of membrane-bound cell-free granules extruded from eosinophils has been long recognized in tissues associated with eosinophilia, including allergic diseases and responses to helminths. Functional capabilities for extracellular granules have recently been demonstrated. Eosinophil granules express cytokine receptors on their membranes and function, upon extrusion from eosinophils, as independent secretory organelles releasing granule constituents in response to activating cytokines and chemokines. We provide an update on the processes that mediate selective protein secretion from within eosinophil granules both as intracellular organelles and, as novelly demonstrated, as cell-free extracellular structures.