Complement activation usually results in the formation of complement fragment 5a (C5a) that interacts with its two receptors, C5aR and C5L2. These receptors belong to the rhodopsin family of G protein-coupled seven transmembrane-containing receptors. C5aR and C5L2 are expressed on/in a wide variety of cells and tissues. Interaction of C5a with C5aR leads to many pleiotropic effects, including the release of cytokines and chemokines and recruitment of inflammatory cells. In certain circumstances, C5a-C5aR interactions can also result in pathophysiological changes as seen in sepsis, rheumatoid arthritis, asthma, acute lung injury and ischemia-reperfusion injury. This overview of the C5a-C5aR interactions describes how such interactions facilitate the pivotal role the complement system plays in the host's innate and adaptive responses.