The transport of methotrexate (MTX) into Walker 256 carcinoma (W256) and hepatoma 5123 (H5123) transplanted in rats was investigated after a pulse injection and continuous infusion of the drug. A mathematical model was developed which adequately described the distribution and transport of MTX in both solid tumors. In H5123 the uptake was limited by the amount of drug carried by plasma (flow-limited transport), but in W256 MTX uptake was limited by the rate at which the drug crossed the tissue barriers (tissue-limited transport). Relative uptake by the solid tumors was almost eightfold more efficient with low than with high doses. MTX concentration in tumor interstitial fluid equilibrated with that of plasma in about 50 hr using a micropore chamber with a diffusion coefficient of 0.5 microm/min as sampling device. MTX concentration was higher in resistant than in responsive tumors.