Secretion is a fundamental cell process underlying different physiological and pathological events. In cells from the human immune system such as eosinophils, secretion of mediators generally occurs by means of piecemeal degranulation, an unconventional secretory pathway characterized by vesicular transport of small packets of materials from the cytoplasmic secretory granules to the cell surface. During piecemeal degranulation in eosinophils, a distinct transport vesicle system, which includes large, pleiomorphic vesiculo-tubular carriers is mobilized and enables regulated release of granule-stored proteins such as cytokines and major basic protein. Piecemeal degranulation underlies distinct functions of eosinophils as effector and immunoregulatory cells. This review focuses on the structural and functional advances that have been made over the last years concerning the intracellular trafficking and secretion of eosinophil proteins by piecemeal degranulation during inflammatory responses.