Murine erythroleukemic cells can be induced to express globin genes and to differentiate by chemical compounds such as dimethylsulfoxide, hemin, butyric acid, hexamethylenebisacetamide. In addition, tumor promoters have been shown to inhibit this induced differentiation, thus suggesting that the conversion of a cell into a cancer cell can be thought as an alteration in its state of differentiation. We found that actinomycin D-induced erythroid differentiation is not inhibited by the tumor promoter 12-0-tetradecanoyl-phorbol-13-acetate (TPA) in two murine erythroleukemia cell lines. Thus we investigated the cellular distribution with respect to the cell cycle in synchronized cells cultured with TPA and actinomycin D in order to determine whether alteration of the cell cycle parameters can interfere to some extent with the process of differentiation. Cells synchronized in S phase progress through the cell cycle and differentiate when cultured with actinomycin D and TPA. On the contrary, some cells synchronized in G1 are prevented entry to S phase by the tumor promoter. Only in this cellular population was there found inhibition of intracytoplasmic hemoglobin accumulation. Therefore in the Friend leukemia cell system, the tumor promoter TPA does not inhibit DNA synthesis, but the progression of the cells through G1. In addition our results suggest that this progression through G1 and/or early S is a cellular event which is critical for the organization of the expression of globin and related genes.