Human hemoglobin, a tetramer containing two α globins and two β globins, is responsible for oxygen transportation in the body. Globin genes are clustered in the genome and their expressions are regulated by a variety of cis-acting elements and trans-acting factors, exhibiting a developmental- and tissue-specific manner. β-thalassemia and sickle cell diseases are two of the most common autosomal recessive disorders caused by mutations in the β-globin gene. Besides α- and β-globins, the human genome also has a third globin gene—γ-globin. Like β-globin, γ-globin also has oxygen-carrying capabilities. Unlike β-globin, γ-globin is mainly expressed at the fetal stage and remains intact in β-thalassemia and sickle cell disease patients. Thus, reactivating the expression of the γ-globin gene in adult patients to ameliorate their clinical symptoms has become one of the best therapeutic strategies to treat β-thalassemia and sickle cell diseases. Some drugs have been developed clinically to increase γ-globin gene expression for those patients. With the development of genome editing technologies, precision gene therapy for these diseases is underway. This review focuses on the main transcription factors and epigenetic modifiers that are involved in γ-globin gene regulation, and some applications for clinical treatment for β-thalassemia and sickle cell diseases based on these studies. We hope to provide a useful reference for in-depth studies on transcriptional regulation of γ-globin gene expression in the future.