We have reviewed erythroid cell differentiation from two points of view: 1) differences between fetal and adult human red cells with particular reference to alterations which can occur in the normal pattern of erythroid cell development during the course of leukemia; 2) beochemical events which occur during erythroid cell maturation, as a model system for the study of the control of gene expression. During the course of many leukemias there is the synthesis of red cells containing fetal hemoglobin. In most cases this phenomenon is limited to a small population or clone of red cells and probably represents a nonspecific response of the bone marrow to a hematologic stress. However, in juvenile chronic myeloid leukemia and, in rare cases of erythroleukemia, there is a major reversion to fetal erythropoiesis, with progressive increase in fetal hemoglobin levels and synthesis of red cells which contain not only fetal hemoglobin but have a true fetal pattern of protein synthesis affecting proteins other than Hb F, namely Hb A2, carbonic anhydrase and the membrane antigens i and I. In this case, the fetal erythropoiesis may be a more specific manifestation of the leukemic process and may be related to the phenomenon of fetal protein synthesis (alpha-fetoprotein of carcinoembryonic antigen) observed in other types of neoplasia. Further information on the etiology and pathogenesis of abnormal cell proliferation and differentiation in the leukemias can be obtained by the study of experimental systems permitting the investigation of the regulation of gene expression in differentiating mammalian cells. Maturing erythroid cells provide a promising system for such investigations for many reasons: differentiating erythroid cells can be obtained relatively free of other cell types; a large amount of a well characterized product, hemoglobin, is synthesized; techniques are now available that permit isolation of erythroid precursors at different stages of differentiation (5-8); and finally, highly sensitive methods of measuring globin mRNA levels by DNA-RNA hybridization are currently available (13, 26, 27). We have used such techniques to measure levels of globin mRNA in separated populations of murine erythroid cells at different stages of maturation. These studies demonstrated a correlation between globin mRNA content and degree of morphological maturation. In the least well differentiated cells, however, there appeared to be a disproportionate amount of mRNA for the level of hemoglobin synthesis in these cells. These results suggest the presence of some translational control of globin mRNA in the early stages of erythroid development, although the major control of globin gene expression in this system seems to be at the transcriptional level...