The erythropoietin tolerance test was used to determine the damaging effect of actinomycin D alone or in combination with X-irradiation upon the hemopoietic stem cells of the polycythemic mouse. When irradiation is administered immediately after actinomycin injection, deleterious effects on the stem cell are additive. Approximately 87 micrograms of actinomycin per kilogram produces the same impairment of response to a standard dose of erythropoietin as does 150 r of total-body irradiation. Although a normal erythropoietic response is obtained on the 4th and 5th days after 87 micrograms actinomycin per kg in these animals, residual damage is observed when the erythropoietic challenge is delayed until the 6th day.