Two calcium-binding proteins, named migration inhibitory factor-related proteins-8 (MRP-8) and MRP-14, are primarily expressed by circulating human neutrophils and monocytes. Evidence accumulating from the investigations of several independent groups is now leading to an improved understanding of the biology of these proteins. Both MRP-8 and MRP-14 display features characteristic of members of the S100 family of calcium-binding proteins. Some of these features predict functions for MRP-8 and MRP-14 but to date an exact and well-defined function remains elusive. Here we review the available information and highlight evidence that suggests the function of MRP-8 and MRP-14 may be associated with both monocyte and neutrophil activation and the accumulation of these cells in inflammatory sites.