In this review we present our current understanding of the role of glucocorticoids in secretory activation and milk secretion by looking at the literature from a historical perspective. We begin with the early endocrine ablation experiments and continue from there to show that glucocorticoids are not just necessary for secretory activation and milk secretion--but mandatory. Specifically, we discuss the importance of glucocorticoids to: (1) induce the formation of ultrastructural components necessary to support milk synthesis and secretion, including rough endoplasmic reticulum and tight junction sealing; (2) regulate milk protein gene expression; and (3) prevent the second phase of involution, possibly by preventing the breakdown of the extracellular matrix.