Secretory proteins play important roles in intercellular communication. The classical secretory protein, which contains a typical signal peptide, is transported through ER-Golgi route. Recently many proteins with a defined extracellular function but lacking signal peptide have been identified and are called non-classical secretory proteins. Increasing evidence shows that the specific mechanisms must be existed for the secretion of the non-classical secretory protein. In this paper, the various secretory mechanisms of the non-classical secretory proteins and the hypotheses on the necessity or advantages of the non-classical secretion were discussed.