The S100A8/S100A9 heterodimer, commonly referred to as calprotectin (CP), is a member of the S100 subfamily of EF-hand calcium binding proteins that is largely expressed in activated monocytes and macrophages and has well-defined functions in acute and chronic inflammation. Indeed, certain S100 proteins including S100A8/A9 are exported from cells by an as-yet unknown mechanism. Once outside the cell, S100A8/A9 activates cell surface receptors such as the receptor for advanced glycation end products (RAGE) and has also been shown to inhibit the growth of pathogenic bacteria through the chelation of trace metal ions such as zinc (Zn2+) and manganese (Mn2+). The binding of these metal ions by S100A8/A9 has also been shown to induce apoptosis in various tumor cell lines. However, several lines of evidence have suggested that S100A8/A9-dependent apoptosis is not solely due to its ability to sequester Zn2+ from cells. Rather, it appears that trace metal binding to S100A8/A9 triggers a novel conformational switch in the protein, which promotes binding to specific sites on the surface of cells or through interaction with yet unidentified cell surface receptors. This review summarizes what is currently known regarding the molecular mechanisms by which S100A8/A9 performs its role as a novel apoptotic agent.