Background: Individuals with sickle cell anemia (SCA) exhibit significant clinical heterogeneity influenced by several factors, including fetal hemoglobin (HbF) levels, which represent a major protective factor in the disease. HbF is formed through the expression of the HBG genes (gamma-globin) during fetal development. Around the time of birth, HBG gene expression is progressively downregulated, leading to HbF silencing in adulthood. However, some SCA patients maintain high HbF levels into adulthood, primarily due to dysregulation of key transcriptional regulators of gamma-globin expression. Aim: This study aims to review the principal transcriptional regulators of HbF expression, along with recently identified regulatory factors. Methodology: A comprehensive literature review was conducted using relevant biomedical databases, focusing on studies published in the last two decades that address molecular mechanisms involved in the regulation of HbF. Results: The repression of HbF is mediated by a complex network of erythroid-specific transcription factors, including GATA-1, BCL11A, SOX6, KLF1, c-Myb, and DNMT1, which interact to form repressor complexes that silence HBG gene expression. KLF1 plays a central role by activating BCL11A, a potent HbF repressor. BCL11A directly binds to the TGACCA motif in the promoter region of HBG genes, thereby repressing gamma-globin expression. The MYB gene, which encodes the transcription factor c-Myb, is a key regulator of hematopoiesis, and it also modulates HbF levels by activating KLF1 and other repressors such as nuclear receptors TR2/TR4. LRF/ZBTB7A, a more recently described factor, binds directly to HBG genes and facilitates transcriptional repression through the recruitment of the NuRD (nucleosome remodeling and deacetylase) complex. Conclusions: Gamma-globin silencing is regulated by several transcriptional repressors that might represent promising therapeutic targets for the induction of HbF in patients with SCA. Advances in gene editing technologies offer the potential to disrupt these repressor pathways and restore HbF expression, improving curative strategies in SCA.