Estrogens play a crucial role in various physiological processes in mammals, including reproduction, cardiovascular health, bone integrity, cognition, and behavior. Given their widespread influence, estrogens are also implicated in the development or progression of numerous diseases, such as various types of cancer, osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, and obesity. The estrogen receptor (ER) is central to these effects, mediating cellular responses through both genomic and nongenomic mechanisms. ERs exist in two main forms, ERα and ERβ, with distinct tissue expression patterns. Selective estrogen receptor modulators (SERMs) and aromatase inhibitors are used therapeutically to target ERs and estrogen production, respectively. The role of ERs in breast, ovarian, colon, prostate, and endometrial cancers is discussed, highlighting the complex interplay between estrogen exposure, ER expression, and disease progression. ERs also influence bone health, with ERβ playing a protective role in osteoporosis. In neurodegenerative diseases, estrogens may provide neuroprotection, but the efficacy of estrogen therapy remains controversial. Cardiovascular diseases are protected by estrogens, but the timing and dosage of treatment are critical. Obesity is influenced by ERs, affecting adipogenesis and lipid metabolism. The chapter concludes by emphasizing the need for further research to optimize therapeutic strategies based on ER function and genetic profiles.Estrogens play a crucial role in various physiological processes in mammals, including reproduction, cardiovascular health, bone integrity, cognition, and behavior. Given their widespread influence, estrogens are also implicated in the development or progression of numerous diseases, such as various types of cancer, osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, and obesity. The estrogen receptor (ER) is central to these effects, mediating cellular responses through both genomic and nongenomic mechanisms. ERs exist in two main forms, ERα and ERβ, with distinct tissue expression patterns. Selective estrogen receptor modulators (SERMs) and aromatase inhibitors are used therapeutically to target ERs and estrogen production, respectively. The role of ERs in breast, ovarian, colon, prostate, and endometrial cancers is discussed, highlighting the complex interplay between estrogen exposure, ER expression, and disease progression. ERs also influence bone health, with ERβ playing a protective role in osteoporosis. In neurodegenerative diseases, estrogens may provide neuroprotection, but the efficacy of estrogen therapy remains controversial. Cardiovascular diseases are protected by estrogens, but the timing and dosage of treatment are critical. Obesity is influenced by ERs, affecting adipogenesis and lipid metabolism. The chapter concludes by emphasizing the need for further research to optimize therapeutic strategies based on ER function and genetic profiles.