Our results may be summarized as follows: 1) The tumor microvasculature is hyperpermeable to macromolecular tracers, as compared with the vessels supplying many normal tissues. 2) In the case of the several solid transplantable animal tumors studied, leaky vessels are well-differentiated venules and small veins, lined by a continuous endothelium with mostly closed interendothelial junctions. Leaky vessels are concentrated at the tumor-host interface and in bands of stroma interspersed between tumor nodules; in contrast, tumor-penetrating vessels exhibit little or no leakage of macromolecules. 3) The mechanisms of vascular leakage have yet to be established but apparently cannot be attributed to vessel immaturity, structural defects, interendothelial cell gaps, vessel injury or development of a specialized (e.g., fenestrated or sinusoidal) endothelium. 4) Macromolecules that extravasate from leaky vessels also accumulate in tumors at higher concentrations than in the blood or control tissues. Increased tracer accumulation in tumors is attributable to increased tracer influx and possibly also to reduced tracer clearance (perhaps resulting from the absence or obstruction of lymphatics). However, the high molecular weight FITC-D tracers that extravasate into solid tumors remain largely confined to tumor stroma, do not extend far from the vessels from which they leaked, and make little contact with malignant cells. 5) In contrast, smaller tracers (e.g., 3 kD FITC-D) extravasate from tumor-penetrating vessels, from the capillaries of normal tissues, as well as from hyperpermeable vessels, and, unlike larger FITC-D, diffuse readily throughout solid tumors.