Activin was discovered in the 1980’s as a gonadal protein that stimulated FSH release from pituitary gonadotropes and was thought of as a reproductive hormone. In the ensuing decades many additional activities of activin were described and it was found to be produced in a wide variety of cell types at nearly all stages of development. Its signaling and actions are regulated intracellularly as well as by extracellular antagonists. Over the past 5 years a number of important advances have been made that clarify our understanding of the structural basis for signaling and regulation, as well as the biological roles of activin in stem cells, embryonic development, and in adults. These include the crystallization of activin in complex with the activin type II receptor ActRIIB, or with the binding proteins follistatin and follistatin-like 3 (FSTL3), and identification of the activin roles in gonadal sex development, follicle development and luteolysis, in β-cell proliferation and function in the islet, in stem cell self-renewal and differentiation into different cell types, and in immune cells. These advances are reviewed to provide perspective for future studies.