Estrogen influences the physiology of many target tissues in both women and men. The long-term effects of estrogen are mediated predominantly by nuclear estrogen receptors (ERs) functioning as DNA-binding transcription factors. Tissue-specific responses to estrogen therefore result from regulation of different sets of genes. However, it remains perplexing as to what regulatory sequence contexts specify distinct genomic responses. First, this review classifies estrogen response sequences in mammalian target genes. Of note, around one third of known human target genes associate only indirectly with ER, through intermediary transcription factor(s). Then, computational approaches are presented both for refining direct ER-binding sites and for formulating hypotheses regarding the overall genomic expression pattern. Surprisingly, limited evolutionary conservation of specific estrogen-responsive sites is observed between human and mouse. Finally, consideration of the cellular functions of regulated human genes suggests links between particular biological roles and specific types of estrogen response elements, although with the important caveat that only a restricted set of target genes is available. These analyses support the view that specific, hormone-driven gene expression programs can result from the interplay of environmental and cellular cues with the distinct types of estrogen-response sequences.