FOXA1 and FOXA2 are transcription factors that regulate gene expression and are involved in various biological processes, including organogenesis, differentiation, glycolipid metabolism, proliferation, migration, invasion, and drug resistance. They may have antagonistic, synergistic, or complementary effects in these processes. This review focuses on the molecular mechanisms and clinical relevance of FOXA1 and FOXA2 in steroid hormone-induced malignancies and highlights potential strategies for targeting these factors in cancer therapy. The article also discusses the potential of targeting upstream regulators of FOXA1/FOXA2 to regulate their expression for cancer therapy, as FOXA1/FOXA2 are not directly targetable by drugs. FOXA1 and FOXA2 have overlapping and non-redundant functions in mammals. They have significant crosstalk in steroid-hormone-associated cancers, including signaling pathways, epigenetic modifications, and post-translational modifications. Both FOXA1 and FOXA2 are involved in cancer resistance, and targeting them can solve the problem of drug resistance. Targeting FOXA1/FOXA2 for cancer therapeutic or preventive purposes has become feasible. The review discusses the roles of FOXA1 and FOXA2 in organ development, glycolipid metabolism, hormone signaling pathway transduction, and cancer drug resistance, as well as their functions as pioneer factors. It also highlights that FOXA1 and FOXA2 have the same or opposite roles in several mammalian stages, providing a theoretical basis for future treatment of metabolic diseases, neurodegenerative diseases, and cancers by targeting FOXA1 and FOXA2. FOXA1 and FOXA2 are essential for the development of organs of endodermal origin, such as the liver, pancreas, lungs, and prostate. They control glucose and lipid metabolism by regulating multiple target genes in the liver, pancreas, and adipose tissue. Mechanistically, the FOXA family of transcription factors maintains enhancer activity and nucleosome localization by opening chromatin structures, making them pioneer factors. FOXA1 and FOXA2 play different biological functions in tumor development by regulating the expression of multiple genes, which are closely related to cancer development and chemoresistance. FOXA1 and FOXA2 are involved in the development of the liver, pancreas, and lung. They promote signal-dependent lineage initiation through enhancer initiation and enhance organ cell-type-specific gene expression through lineage-specific recruitment of transcription factors. In the prostate, FOXA1 and FOXA2 are crucial for the regulation of prostate morphogenesis and cellular differentiation. In the mammary gland, FOXA1 is required for estrogen receptor alpha (ERα) expression and functional activity, which is essential for mammary gland development and ductal morphogenesis. FOXA1 and FOXA2 also play a key role in neuronal development. Knockout of FOXA1/2 in mouse dopaminergic neurons leads to functional alterations, such as severe food intake deficiencyFOXA1 and FOXA2 are transcription factors that regulate gene expression and are involved in various biological processes, including organogenesis, differentiation, glycolipid metabolism, proliferation, migration, invasion, and drug resistance. They may have antagonistic, synergistic, or complementary effects in these processes. This review focuses on the molecular mechanisms and clinical relevance of FOXA1 and FOXA2 in steroid hormone-induced malignancies and highlights potential strategies for targeting these factors in cancer therapy. The article also discusses the potential of targeting upstream regulators of FOXA1/FOXA2 to regulate their expression for cancer therapy, as FOXA1/FOXA2 are not directly targetable by drugs. FOXA1 and FOXA2 have overlapping and non-redundant functions in mammals. They have significant crosstalk in steroid-hormone-associated cancers, including signaling pathways, epigenetic modifications, and post-translational modifications. Both FOXA1 and FOXA2 are involved in cancer resistance, and targeting them can solve the problem of drug resistance. Targeting FOXA1/FOXA2 for cancer therapeutic or preventive purposes has become feasible. The review discusses the roles of FOXA1 and FOXA2 in organ development, glycolipid metabolism, hormone signaling pathway transduction, and cancer drug resistance, as well as their functions as pioneer factors. It also highlights that FOXA1 and FOXA2 have the same or opposite roles in several mammalian stages, providing a theoretical basis for future treatment of metabolic diseases, neurodegenerative diseases, and cancers by targeting FOXA1 and FOXA2. FOXA1 and FOXA2 are essential for the development of organs of endodermal origin, such as the liver, pancreas, lungs, and prostate. They control glucose and lipid metabolism by regulating multiple target genes in the liver, pancreas, and adipose tissue. Mechanistically, the FOXA family of transcription factors maintains enhancer activity and nucleosome localization by opening chromatin structures, making them pioneer factors. FOXA1 and FOXA2 play different biological functions in tumor development by regulating the expression of multiple genes, which are closely related to cancer development and chemoresistance. FOXA1 and FOXA2 are involved in the development of the liver, pancreas, and lung. They promote signal-dependent lineage initiation through enhancer initiation and enhance organ cell-type-specific gene expression through lineage-specific recruitment of transcription factors. In the prostate, FOXA1 and FOXA2 are crucial for the regulation of prostate morphogenesis and cellular differentiation. In the mammary gland, FOXA1 is required for estrogen receptor alpha (ERα) expression and functional activity, which is essential for mammary gland development and ductal morphogenesis. FOXA1 and FOXA2 also play a key role in neuronal development. Knockout of FOXA1/2 in mouse dopaminergic neurons leads to functional alterations, such as severe food intake deficiency