In the 1970s and 1980s, Orkin conducted research that identified genetic mutations associated with a group of blood disorders known as the thalassemias.This work led to the first comprehensive description of molecular defects in an inherited disorder. Later (1986), he and his team cloned a gene causing chronic granulomatous disease, marking the first time that a disease-causing gene was cloned without the researchers already knowing the protein coded by the gene. Today, his research lab examines transcriptional regulators of cell specification and differentiation. His laboratory cloned the first hematopoietic transcription factor GATA1 (1989). Starting in 2008, Orkin and his colleagues published a series of papers identifying the critical role for BCL11A in the developmental switch from fetal type (HbF) to adult type (HbA) hemoglobin. His group demonstrated that loss of BCL11A alone is sufficient to rescue the phenotype of sickle cell disease (SCD). In September 2015, Orkin published a study in the journal Nature showing a small section of DNA which could be responsive to gene therapy for sickle-cell disease. Translation of the basic findings on the role of BCL11A in HbF silencing to the clinic is ongoing both with gene therapy and therapeutic gene editing.