The Orkin laboratory has focused on transcriptional control in the hematopoiesis for several decades, including studies of the role of specific transcription factors in lineage determination and stem cell functions. More recently, our work has revealed how the switch from fetal (HbF) to adult hemoglobin (HbA) is controlled by the repressor BCL11A, and demonstrated how to leverage CRISPR gene editing to cripple BCL11A expression and reactivate HbF. These discoveries have been translated by biotech/pharma in clinical trials to treat patients with sickle cell disease and beta-thalassemia. Because gene editing, as currently employed, will not reduce the burden of disease more widely, we now seek to use small molecules to reactivate HbF based on what has been learned regarding the mechanism of action of BCL11A and regulation of its expression in erythroid cells. Our research entails interdisciplinary studies incorporating molecular and cell biology, chemistry, and structural biology.