['The induction of fetal hemoglobin during definitive erythropoiesis is a major therapeutic goal in β-globin gene disorders. Butyrate induces fetal hemoglobin, and p38 phosphorylation has been implicated in this process. We studied p38 and the effect of its inhibitors in a physiologic primary cell model of fetal/embryonic globin gene induction during definitive erythropoiesis.', 'p38 phosphorylation was evaluated in a short-term culture of definitive erythroid precursor (EryD) cells following butyrate induction, absent prolonged exposure to cytokines. The impact of p38 inhibitors on embryonic/fetal globin gene induction by butyrate and on normal erythroid processes, including proliferation, differentiation, cell cycle occupancy, and RNA transcription, was also examined.', 'p38 phosphorylation, maximal at harvest of murine fetal liver-derived EryD (FL EryD), when minimal embryonic/fetal globin gene expression is seen, is suppressed by EPO (as reported by others). Butyrate initially delays EPO-mediated suppression of p38 phosphorylation, but p38 phosphorylation thereafter, at 30 minutes to 48 hours, is equivalent and at low levels in EPO-treated FL EryD, with or without butyrate. Inhibitors of p38, at 10-50 μM, prevent butyrate-mediated induction of embryonic/fetal globin gene expression. We found that p38 inhibitors, which also disrupt non-p38 signaling pathways, perturb cell division, erythroid differentiation, transit through the cell cycle, and RNA transcription in primary EryD.'] Does induction of fetal/embryonic globin gene expression depend on intact cell signaling in definitive erythroid cells?