Estrogen receptor-α (ERα) is a protein with a long history of study that precedes the advent of modern molecular biology. Over the course of 50 years, ERα has been increasingly recognized as a prominent model for the study of the mechanism of gene transcription in vertebrates. It also serves as a regulatory molecule for numerous physiological and disease states. Several fundamental insights have been made using ERα as a model protein, from the discovery that endocrine hormones elicit gene transcription to our understanding of the relationship between ERα-mediated transcription and transcription factor degradation by the ubiquitin proteasome system (UPS). Understanding of receptor protein degradation developed alongside other aspects of its molecular biology, from early observations in the 1960s that ERα is degraded on hormone treatment to the current understanding of ERα transcriptional regulation by the UPS. Here, we present the concept of ERα turnover from the perspective of the historical development of this notion and highlight some of the latest discoveries regarding this process. We discuss the logic and significance of ERα degradation pathways in the context of cell and whole-organism homeostasis.