Estrogen regulates many different and sometimes quite opposite processes in cells. Since the discovery of estrogen receptor (ER), the last few decades have resulted in a better understanding of estrogen biology. Estrogen is involved in processes leading to different pathologies in estrogen responsive tissues, not only carcinogenesis, but this was one of the most investigated fields in estrogen-related pathology. The exact role of estrogen in these pathologies is not completely understood due to the complex interplay of its receptors with other signaling pathways. This review considers the latest literature focused on estrogen and ERs as potential therapeutic targets in the treatment of malignant disease (e.g. breast, prostate, ovarian and endometrial cancer).