Sickle cell disease (SCD) and β-thalassemia are common, life-threatening anemias caused by mutations in the HBB gene, which encodes the β-globin subunit of adult hemoglobin (HbA, α2β2). These diseases become symptomatic shortly after birth, as expression of the normal fetal γ-globin genes (HBG1 and HBG2) declines and the mutant HBB gene is activated in red blood cell (RBC) precursors. However, the γ-globin genes are incompletely silenced, leading to variable levels of fetal hemoglobin (HbF, α2γ2), which can alleviate β-hemoglobinopathies in a dose-dependent manner. At the extreme end of the spectrum, a rare, benign genetic condition known as hereditary persistence of fetal hemoglobin (HPFH) causes high-level postnatal HbF expression, which eliminates the symptoms of co-inherited SCD or β-thalassemia. These early clinical observations sparked more than 50 years of intensive efforts to understand globin gene regulation and therapeutically recapitulate HPFH. Now, the transcription factors and cis elements that coordinate the perinatal γ-globin-to-β-globin gene switch are largely defined, and we are beginning to understand the associated epigenetic regulation, including recent findings that developmentally regulated DNA methylation at key CpG motifs in the γ-globin or β-globin gene promoters directly silences transcription of the corresponding gene and that targeted demethylation can activate gene expession. I will discuss how recent insights into globin gene regulation are synergizing with genome engineering technologies to fuel novel gene therapies for β-hemoglobinopathies and to elucidate general mechanisms of transcriptional regulation.