Tumor blood supply was related to the morphology of the tumor microvasculature and the supplying arteries (SAs) of A-07-GFP and D-12-GFP melanoma xenografts growing in window chamber preparations in BALB/c nu/nu mice. Blood supply and morphologic parameters were determined from first-pass imaging movies and vascular maps recorded after a bolus of 155-kDa tetramethylrhodamine isothiocyanate-labeled dextran had been administered intravenously. Poorly supplied tumors showed microvascular networks that did not differ from those of well-supplied tumors in vessel tortuosity, diameter, and density. Conversely, the SAs of poorly supplied tumors were more tortuous and had a smaller diameter than those of well-supplied tumors, resulting in lower plasma velocities in the downstream tumor vessels. Consequently, the blood supply of A-07-GFP and D-12-GFP tumors was governed by the geometric resistance of the SAs rather than by the geometric resistance or the vessel density of the tumor microvasculature. The present study suggests that the SAs may represent an important target for physiological interventions of tumors and that it may be beneficial to focus on the tumor SAs rather than the tumor microvasculature when searching for novel therapeutic strategies for modifying tumor blood supply.