Serglycin is a proteoglycan composed of a relatively small (~17 kDa) core protein to which sulfated glycosaminoglycans of either heparin, heparan sulfate or chondroitin sulfate types are attached. Serglycin is expressed in many cell types, including in particular cells of hematopoietic origin. To study the function of serglycin, we have used a serglycin knockout mouse strain. A striking finding was that the mast cell population was severely affected by the absence of serglycin, as evidenced by distorted granule morphology and defective staining with cationic dyes. Moreover, the absence of serglycin caused a dramatic effect on the ability of mast cells to store a number of granule compounds, including several mast cell-specific proteases as well as biogenic amines. Hence, serglycin has a major function in maintaining mast cell secretory granule homeostasis.