The cysteinyl leukotrienes (cys-LTs), leukotriene (LT) C₄, LTD₄, and LTE₄, are smooth muscle constrictors that signal via the CysLT₁ receptor. Here we report that the cys-LTs play an important role in chronic pulmonary inflammation with fibrosis induced by bleomycin in mice. Targeted disruption of LTC₄ synthase, the pivotal enzyme for cys-LT biosynthesis, protected significantly against alveolar septal thickening by macrophages and fibroblasts and collagen deposition. In contrast, targeted disruption of the CysLT₁ receptor significantly increased both the concentration of cys-LTs in the bronchoalveolar lavage fluid and the magnitude of septal thickening as defined by morphology, digital image analysis, and deposition of reticular fibers. These findings change our understanding of the pathobiology mediated by the cys-LTs by revealing their role in chronic inflammation with fibrosis, likely via the CysLT₂ receptor, and by uncovering a dual role for the CysLT₁ receptor, namely proinflammatory acute constriction of smooth muscle and antiinflammatory counteraction of chronic injury.