The lipid mediator prostaglandin D(2) (PGD(2)) has long been implicated in various inflammatory diseases including asthma. PGD(2) elicits biological responses by activating two seven-transmembrane (7TM) G-protein-coupled receptors, the D-prostanoid receptor DP and the chemoattractant receptor homologous-molecule expressed on T-helper-type-2 cells (CRTH2), which are linked to different signaling pathways. Understanding how immune cells integrate and coordinate signals that are triggered by the same ligand is crucial for the development of novel anti-inflammatory therapies. Here, we examine the roles of DP and CRTH2 in the orchestration of complex inflammatory processes, and discuss their importance as emerging targets for the treatment of asthma and inflammatory diseases.