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Measurements of methotrexate transport in L1210 cells in the presence and absence of D-glucose reveal that both influx and efflux are depressed in the absence of D-glucose, whereas the steady-state accumulation of drug is enhanced. The reason for the increase in steady state is that the relative decline in efflux is greater than the decline in influx. Analysis of the concentration dependence of steady-state methotrexate accumulation in D-glucose-deprived cells indicates a linear relationship consistent with a one-carrier active transport model. Similar data in nondeprived cells is highly nonlinear and strongly supports the postulate that under physiological conditions influx and efflux of methotrexate are mediated by separate carrier systems. These results indicate that the efflux system, preferentially transporting methotrexate under normal conditions, cannot operate in the absence of D-glucose, whereas the influx system is only partially inhibited under conditions of glucose deprivation.