Kawasaki disease (KD) is the most common cause of multisystem vasculitis in childhood. Its propensity for aneurysm formation makes KD quite unique among coronary artery diseases, and the leading cause of pediatric acquired heart disease in the developed world. Tumour necrosis factor-alpha (TNFalpha) is a pleiotropic inflammatory cytokine elevated during the acute phase of KD. In a murine model of KD, rapid TNFalpha production occurs in the peripheral immune system after disease induction. This immune response becomes site-directed, with migration to coronary arteries dependent on TNFalpha mediated events. Production of TNFalpha in the heart is coincident with the presence of inflammatory infiltrate at the coronary arteries, which persists during aneurysm development. Ablation of TNFalpha effector functions abrogated inflammation and elastin breakdown in coronary vessels, rendering mice resistant to coronary arteritis and aneurysm formation. Thus, TNFalpha is necessary for development of coronary artery lesions in an animal model of Kawasaki disease.