S1A8 is a member of the S1 protein family containing 2EF-hand calcium-binding motifs. S1 proteins are involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. Altered expression of S1A8 protein is associated with various diseases and cancers. S1A8 may have an immunoregulatory role by contributing to the regulation of fetal-maternal interactions. It may play a protective role and its absence may allow infiltration by maternal cells, a process eventually manifesting as resorption. The heterodimeric S1 protein complex S1A8/A9 which has been shown to be involved in inflammatory and neoplastic disorders. The complex can induce cell proliferation, or apoptosis, inflammation, collagen synthesis, and cell migration. S1A8/A9 has emerged as important pro-inflammatory mediator in acute and chronic inflammation. More recently, increased S1A8 and S1A9 levels were also detected in various human cancers, presenting abundant expression in neoplastic tumor cells as well as infiltrating immune cells. On the one hand, S1A8/A9 is a powerful apoptotic agent produced by immune cells, making it a very fascinating tool in the battle against cancer. It spears the risk to induce auto-immune response and may serve as a lead compound for cancer-selective therapeutics. In contrast, S1A8/A9 expression in cancer cells has also been associated with tumor development, cancer invasion or metastasis. Altogether, its expression and potential cytokine-like function in inflammation and in cancer suggests that S1A8/A9 may play a key role in inflammation-associated cancer.