Abstract: Estrogen receptor(ER), one member of the nuclear receptor superfamily, via binding to estrogen, plays important roles in development and metabolism of human tissues and organs as well as a number of diseases, such as cancer, obesity, diabetes and osteoporosis. Co-regulators, one important kind of factors in the ER transcriptional signaling, increase(as co-activators) or reduce(as co-repressors)ER-mediated transcriptional activity via direct and indirect binding to ER. Increasing evidence has revealed that a short α-helical sequence LXXLL motif(where L is leucine, X is any amino acid), widely present in many co-regulators, especially co-activators, plays an essential or necessary role in co-regulator interaction with ER. To explore the involved mechanism(s) will be helpful in understanding the critical role of LXXLL motif in the interaction of co-regulators and ER. This review briefly describes the potential roles of LXXLL motif in the involvement of ER co-regulators in modulation of ER signaling and underlying mechanisms as well as current progress in developing pharmaceutical agents that modulate ER-coregulator interaction via specifically targeting LXXLL motifs in therapy of hormone-associated cancers.