Awareness of estrogen's neuroprotective and behavioral effects is broadening rapidly and has served as an incentive to investigate estrogen signaling in central nervous system disorders. The present analysis focuses on two human nuclear estrogen receptors, ER alpha and ER beta, which have been shown to play key roles in the complex integration of estrogen's genomic and non-genomic modes of action. The corresponding genes are estimated to have diverged from an ancestral ER gene over 450 million years ago and are candidate genes for a variety of brain disorders. Recent progress in the Human Genome Project has greatly aided our understanding of the molecular blueprint and provides the means for reassessing both genes' genomic organization. Analyses of multiple alternatively spliced transcripts, large untranslated sequences and neighbouring genes reveal several novel features which suggest an increasingly versatile transcriptional machinery. We outline additional exons in the genes' 5'- and 3'-untranslated regions, a new polymorphic ER alpha microsatellite and a nested gene which lend themselves to further evolutionary and functional studies.