The article reviews the regulatory mechanisms and therapeutic implications of FOXA1 and FOXA2 in cancer. FOXA1 and FOXA2 are pioneering transcription factors that play crucial roles in organogenesis, differentiation, glycolipid metabolism, proliferation, migration, invasion, and drug resistance. They exhibit both overlapping and non-redundant functions, with crosstalk in steroid-hormone-associated cancers. Targeting FOXA1 and FOXA2 for cancer therapy is feasible, and strategies to target upstream regulators of these proteins are also discussed. The article highlights their roles in prostate cancer, breast cancer, and liver cancer, emphasizing their involvement in lineage plasticity, drug resistance, and metabolic regulation. FOXA1 and FOXA2 are found to interact with androgen receptors and estrogen receptors, influencing gene expression and cellular processes. In prostate cancer, FOXA1 and FOXA2 are involved in androgen receptor signaling and drug resistance. In breast cancer, FOXA1 and FOXA2 affect ERα signaling and EMT. In liver cancer, they influence sex dimorphism and carcinogenesis. The article also discusses the potential therapeutic targets and strategies for targeting FOXA1 and FOXA2 in various cancers, including combination therapies and the role of upstream regulators.The article reviews the regulatory mechanisms and therapeutic implications of FOXA1 and FOXA2 in cancer. FOXA1 and FOXA2 are pioneering transcription factors that play crucial roles in organogenesis, differentiation, glycolipid metabolism, proliferation, migration, invasion, and drug resistance. They exhibit both overlapping and non-redundant functions, with crosstalk in steroid-hormone-associated cancers. Targeting FOXA1 and FOXA2 for cancer therapy is feasible, and strategies to target upstream regulators of these proteins are also discussed. The article highlights their roles in prostate cancer, breast cancer, and liver cancer, emphasizing their involvement in lineage plasticity, drug resistance, and metabolic regulation. FOXA1 and FOXA2 are found to interact with androgen receptors and estrogen receptors, influencing gene expression and cellular processes. In prostate cancer, FOXA1 and FOXA2 are involved in androgen receptor signaling and drug resistance. In breast cancer, FOXA1 and FOXA2 affect ERα signaling and EMT. In liver cancer, they influence sex dimorphism and carcinogenesis. The article also discusses the potential therapeutic targets and strategies for targeting FOXA1 and FOXA2 in various cancers, including combination therapies and the role of upstream regulators.