We have analyzed the chromatin structure of the human beta-globin locus in somatic cell hybrids resulting from the fusion of human non-erythroid cells and mouse erythroleukemia (MEL) cells. In these hybrids, the human adult beta-globin gene, but neither the embryonic nor fetal globin genes, is activated transcriptionally. In addition, the DNase I-resistant beta-like globin locus characteristic of the parental non-erythroid human cells (1,2) is reorganized over an approximately 80 kb region, including the formation of the developmentally stable hypersensitive sites 50 kb 5' and 20 kg 3' of the activated adult beta-globin gene (2,3). These results are consistent with the hypothesis that events occurring at the 5' and/or 3' developmentally stable hypersensitive sites are important, if not necessary, for the activation of the beta-globin locus.