Neutrophils are rapidly recruited to sites of inflammation and are thereby at the forefront of the organism's defense against numerous attacks. As unspecific phagocytes, they belong to the so‐called innate immunity. Two S100 proteins, namely S100A9 (MRP14) and S100A8 (MRP8), constitute roughly 40% of the cytosolic protein in these cells, implying by their pure abundance an important role in the effector functions of neutrophils. However, despite intense research in the past 15 years, the puzzle that may embed both molecules into the neutrophil/monocyte physiology is still incomplete. One reason might be the conformational variability the S100A9 and S100A8 molecules can adopt. They readily form hetero‐ and homodimeric, trimeric as well as tetrameric complexes, but they evidently do also exert specific functions as monomers. An ever‐increasing body of information suggests that S100A9 plays a prominent role in leukocyte trafficking and arachidonic acid metabolism. In addition, elevated levels of S100A9 and S100A8 in body fluids of inflamed tissues strengthen the view that these molecules are important players in fighting inflammation. The aim of this review is to give an update on the current developments concerning the S100A9/S100A8 molecule in biology and medicine. Microsc. Res. Tech. 60:569–580, 2003. © 2003 Wiley‐Liss, Inc.