The classical C5a receptor (C5aR, CD88) belongs to the group of seven-transmembrane spanning rhodopsin family of receptors that signal through G-protein-dependent path-ways (reviewed in Guo et al. 2004) . Originally, C5aR was presumed to be expressed exclusively on myeloid cells but now there is ample evidence that it can be expressed on a variety of non-myeloid cells (Wetsel 1995) . Under inflammatory conditions, expression of C5aR increases in lung endothelial, alveolar and bronchial epithelial cells and macrophages Riedemann et al. 2002) . The recently identified C5L2 receptor for C5a is also a seven-transmembrane spanning rhodopsin family receptor. Abundant expression of C5L2 has been found on neutrophils and dendritic cells (Ohno et al. 2000) . Unlike C3aR and C5aR, C5L2 is uncoupled from G-proteins due to an amino-acid replacement of arginine by leucine in the DRY region at the end of the third intra-cellular transmembrane loop (Cain and Monk 2002) . Following binding of C5a, C5L2 does not induce classical signaling (induction of intracellular calcium transients) or cause biological cellular responses. The role of C5L2 is largely unknown. It may act as a decoy or scavenger receptor for C5a (Okinaga et al. 2003; Scola et al. 2009 ). However, recent studies suggest that C5L2 acts as a functional receptor especially in the setting of sepsis where release of high mobility group box 1 protein requires the presence of C5L2 receptor on macrophages. Blockade of C5L2 along with C5aR greatly improves survival in sepsis when compared to blockade of either receptor alone (Rittirsch et al. 2008a ). Under such conditions, there is a broad suppression in levels of cytokines and chemokines in plasma.