Abstract: Estrogens act by binding to and activating two estrogen receptors (ERs): ERα and ERβ. Estrogens control many cellular processes, including the growth, differentiation, and function of the reproductive system. Recently, numerous studies reported on the functions of ERβ in tumors. However, the results of these studies remain controversial. The discovery of different isoforms (i.e., ERβ-1 to ERβ-5) is likely to explain the conflicting points-of-view. It will also increase our knowledge about the molecular basis of ERβ signaling, including the unknown physiological functions of these ERβ isoforms. Improved insights into the physiology, pathophysiology, and molecular biology of ERβ-mediated signaling may lead to the identification of novel targets for the effective therapeutic intervention against estrogen-related diseases. This review will provide an overview of the most recent advances in the identification of the ER β-1 to ERβ-5 isoforms in relation to cancer.