Tissue injury induced by a diverse group of xenobiotics appears to involve both direct and indirect damage to target cells. Thus, while chemicals may act directly on target cells resulting in toxicity, they may also act indirectly by recruiting and activating resident and inflammatory tissue macrophages. Macrophages are potent secretory cells that release an array of mediators, including proinflammatory and cytotoxic cytokines and growth factors, bioactive lipids, hydrolytic enzymes, reactive oxygen intermediates, and nitric oxide--each of which has been implicated in the pathogenesis of tissue injury. The potential role of macrophages and their mediators in tissue injury has been extensively investigated in the lung and the liver. In both of these tissues, xenobiotics induce localized macrophage accumulation and mediator release. Furthermore, when macrophage functioning is blocked, pulmonary and hepatic injury-induced agents such as ozone, bleomycin, acetaminophen, carbon tetrachloride, and galactosamine are reduced. These data provide direct support for the hypothesis that macrophages and the mediators they release contribute to xenobiotic-induced tissue injury.