Pulmonary dysfunction is one of the most frequent complications associated with cardiopulmonary bypass (CPB). Multiple factors, including the contact of blood with the artificial surface of the CPB circuit, ischemia-reperfusion and lung ventilator arrest elicit inflammatory reactions, consequently resulting in CPB-induced lung injury. The proinflammatory cytokine tumor necrosis factor- (TNF-) has been demonstrated to have a critical role in mediating CPB-induced pulmonary inflammation. The present review evaluated previous studies and summarized the effects of CPB on TNF- level in the serum and lung tissue of patients and animal models of CPB, the underlying mechanism of TNF--mediated lung injury and the therapeutic strategies for the inhibition of TNF- activity and production to attenuate CPB-induced lung injury. TNF- level in the serum and lung tissue is significantly increased during and following CPB. TNF- mediates CPB-induced lung damage by directly inducing apoptosis in alveolar epithelial cells and lung endothelial cells and by indirectly modulating the function of immune cells, including monocytes and macrophages. A functional neutralizing antibody to TNF- can reduce pulmonary TNF- production and attenuate CPB-induced lung injury in a rabbit model of CPB. Inhibition of TNF- function and production using a neutralizing antibody to TNF- appears to be a promising therapeutic strategy to alleviate CPB-induced lung injury.