Oestrogen receptor-α (ERα) is a master transcription factor that regulates cell proliferation and homeostasis in many tissues. Despite beneficial ERα functions, sustained oestrogenic exposure increases the risk and/or the progression of various cancers, including those of the breast, endometrium and ovary. Oestrogen–ERα interaction can trigger post-translational ERα modifications through crosstalk with signalling pathways to promote transcriptional activation and ubiquitin-mediated ERα proteolysis, with co-activators that have dual roles as ubiquitin ligases. These processes are reviewed herein. The elucidation of mechanisms whereby oestrogen drives both ERα transactivation and receptor proteolysis might have important therapeutic implications not only for breast cancer but also potentially for other hormone-regulated cancers.