Abstract Estrogen receptors (ER) classically function as transcription factors regulating gene expression. More recently, evidence has continued to accumulate that ER additionally serve numerous important functions remote from the nucleus in a variety of cell types, particularly in non-reproductive tissues. The identification of post-translational modifications of ERα and protein–protein interactions with the receptor that are critical to its non-nuclear functions has afforded opportunities to gain greater insights into these novel non-genomic roles of the receptor. The development of a stable ligand that selectively activates non-nuclear ER has also been invaluable. In this review focused on ERα, recent new understanding of the processes underlying non-nuclear ER action and their in vivo consequences will be discussed. Further research into the non-nuclear capacities by which ER modulate cellular behavior is essential to ultimately harnessing these processes for therapeutic gain in numerous disease contexts.