Chemical modulation of tumor blood flow has until recently received relatively little attention as a therapeutic tool. Developments in the last few years, both in technology and in drug development, have changed this perspective. Fluorescence activated cell sorting techniques have provided evidence for the existence of acutely hypoxic cells resulting from transient fluctuations in microregional tumor blood flow in experimental tumor systems. We have used such techniques to assess the effects of three systemically administered agents, nicotinamide, flunarazine and Flusol-DA, on the amount of acute hypoxia in the SCCVII tumor. The most effective agent identified in this study is the benzamide analog nicotinamide. We suggest that compounds which modulate such hypoxia could well have a role in radiation therapy, particularly when combined with techniques which increase the oxygen carrying capacity of the blood. The potential of tumor blood flow reduction to improve the effectiveness of bioreductive agents administered alone or in combination with radiation and/or hyperthermia, is well established in experimental systems. Further data are presented, which show that combining hydralazine and the beta-blocker propranolol can provide greater reduction in tumor blood flow than observed with hydralazine alone. Potential limitations of drug induced reduction in tumor blood flow are discussed including the possibility of inducing hypoxia in normal tissues.