The article discusses the multifaceted mechanisms of estradiol (E2) and estrogen receptor (ER) signaling, focusing on the roles of ERα and ERβ. E2, a key regulator of growth, differentiation, and function in various tissues, primarily acts through these two intracellular receptors. While ERα and ERβ share high homology in their DNA- and ligand-binding domains, they exhibit distinct expression patterns and functions. ERα is predominantly expressed in the breast, uterus, cervix, and other reproductive and target organs, whereas ERβ is more limited to the ovary, prostate, testis, and other tissues. The phenotypes of ER knockout mice (αERKO and βERKO) reflect these distinct expression patterns, with αERKO showing estrogen insensitivity and hypergonadism, while βERKO females exhibit subfertility. The article reviews four main pathways of estrogen signaling: classical ligand-dependent, ligand-independent, DNA binding-independent, and cell-surface (nongenomic) signaling. It highlights the role of coactivators and corepressors in these pathways and discusses the mechanisms of action of selective estrogen receptor modulators (SERMs). The article also explores the ligand-independent activation of ER by growth factors and the nongenomic effects of estrogens, emphasizing the importance of understanding these mechanisms for developing targeted pharmaceuticals.The article discusses the multifaceted mechanisms of estradiol (E2) and estrogen receptor (ER) signaling, focusing on the roles of ERα and ERβ. E2, a key regulator of growth, differentiation, and function in various tissues, primarily acts through these two intracellular receptors. While ERα and ERβ share high homology in their DNA- and ligand-binding domains, they exhibit distinct expression patterns and functions. ERα is predominantly expressed in the breast, uterus, cervix, and other reproductive and target organs, whereas ERβ is more limited to the ovary, prostate, testis, and other tissues. The phenotypes of ER knockout mice (αERKO and βERKO) reflect these distinct expression patterns, with αERKO showing estrogen insensitivity and hypergonadism, while βERKO females exhibit subfertility. The article reviews four main pathways of estrogen signaling: classical ligand-dependent, ligand-independent, DNA binding-independent, and cell-surface (nongenomic) signaling. It highlights the role of coactivators and corepressors in these pathways and discusses the mechanisms of action of selective estrogen receptor modulators (SERMs). The article also explores the ligand-independent activation of ER by growth factors and the nongenomic effects of estrogens, emphasizing the importance of understanding these mechanisms for developing targeted pharmaceuticals.