SUMMARY The distribution of methotrexate between tissues is a very complex process, dependent in part upon the species studied, the size of the dose and the channel of administration. The nature of the tissue and its content of dihydrofolate reductase also play a part. Elimination of methotrexate in the urine and bile indicate that renal and hepatic function are also important. The amounts of administered methotrexate taken up by the skin and liver were doubled by experi-mental folate depletion. In contrast, folate deficiency did not significantly increase uptake by the kidneys or intestines. The skin uptake of methotrexate was increased about six-fold by prior strip-ping, without infiuencing the hepatic uptake. Methotrexate taken up could be partially displaced by pteridines which have affinity for dihydrofolate reductase. Methotrexate itself was most efficient, but both dihydrofolate and folic acid were more effective than leucovorin, while 5-methyl folate had virtually no effect. These results indicate that a risk of hepatic injury is probably inseparable from the therapeutic action of methotrexate in psoriasis, even though the amount of drug reaching the liver can be reduced by using a logical parenteral schedule.