Prostaglandin D₂, the ligand for the G-protein coupled receptors DP1 and CRTH2, has been implicated in the pathogenesis of the allergic response in diseases such as asthma, rhinitis and atopic dermatitis. This prostanoid also fulfills a number of physiological, anti-inflammatory roles through its receptor DP1. We investigated the role of PGD₂ and CRTH2 in allergic pulmonary inflammation by using a highly potent and specific antagonist of CRTH2. Administration of this antagonist ameliorated inflammation caused by either acute or sub-chronic sensitization using the cockroach egg antigen (CRA). Gene expression and ELISA analysis revealed that there was reduced proinflammatory cytokine mRNA or protein produced, as well as a wide array of genes associated with the Th2-type pro-inflammatory response. Importantly, the CRTH2 antagonist reduced antigen-specific IgE, IgG1 and IgG2a antibody levels as well as decreased mucus deposition and leukocyte infiltration in the large airways. Collectively, these findings suggest that the PGD₂-CRTH2 activation axis has a pivotal role in mediating the inflammation and the underlying immune response in a T-cell-driven model of allergic airway inflammation.