Antiangiogenic or metronomic chemotherapy, the frequent administration of conventional cytotoxic agents at low doses, is believed to target activated tumor endothelial cells. The mechanisms of action of such regimen remain poorly understood. In the March 2004 issue of Cancer Research, Hamano et al. demonstrated that low-dose cyclophosphamide inhibits tumor growth by upregulating the endogenous angiogenesis inhibitor thrombospondin-1 in tumor and perivascular cells. Thrombospondin-1, in turn, promotes endothelial cell apoptosis. It was also proposed that thrombospondin-1 levels might be used as a surrogate marker to monitor response to low-dose cyclophosphamide therapy in the clinic.