The members of the nuclear receptor superfamily act as transcriptional regulatory factors and exhibit a multidomain structure characterized as domains A-E/F. This review focuses on a small, relatively understudied region at the extreme carboxy-terminus of the estrogen receptor (ER) alpha, the F domain. The F domain contributes to differences in the activity of ER alpha and beta subtypes; it is required for tamoxifen's agonist activity on an estrogen response element, and it modifies the receptor's interactions with coregulators including steroid receptor coactivator-1. The differences between the F domains of the ER alpha and beta subtypes and among the other members of the nuclear hormone receptor superfamily may offer opportunities for selective control of the activity of these proteins.