Secretory leukocyte peptidase inhibitor (SLPI) belongs to the whey acidic protein four-disulfide core family of proteins, and has antimicrobial and antiprotease functions. SLPI is produced by the epithelial cells lining the respiratory, digestive, and reproductive tracts. Gene-targeting experiments in mice indicated that one function of SLPI is to protect proepithelin from elastase cleavage in wound healing. In addition to its antiprotease function, SLPI has an anti-inflammatory function through the modulation of nuclear factor-kappaB acting intracellularly, especially in macrophages. SLPI is also produced in cancer tissues, but its role in cancer is not well understood. SLPI genes are often upregulated under tumorigenic conditions. We found a negligible number of tumors in the lungs of SLPI knockout mice 20 or 40 weeks after administration of urethane, an interesting experimental model for investigating the function of SLPI in cancer. This review discusses the normal function of SLPI and its possible roles in cancer tissues.