Intercellular communication is fundamental in many biological processes involved in cell growth, differentiation, development, and reproduction of living organisms, and secretory proteins are among the most important messengers in this network of information. The vast majority of extracellular proteins are exported from cells by the endoplasmic re-ticulum/Golgi-dependent secretory pathway. However, increasing evidence shows that there are a group of secretory pro-teins without signal peptides, defined as nonclassical secretory proteins, which are exported via an ER/Golgi-independent pathway to perform extracellular functions. This pathway has been termed nonclassical or unconventional secretion, which is an essential and beneficial supplement to the ER-Golgi secretion pathway. The nonclassical secretion pathway has close relation with cell multiplication, immune response, tumor formation, infection pathology and so on. Here, the characters, the possible secretory mechanism, and the biological significance of nonclassical secretory proteins were reviewed.