Selective estrogen receptor modulators (SERMs), known previously as “antiestrogens”, are a new category of therapeutic agents used for the prevention and treatment of diseases such as osteoporosis and breast cancer. SERMs act as ERagonist in some tissues while acting as ER-antagonist in others based on conformational change of the receptors, particularly at the helix 12. Currently, there are two classes of clinically approved SERMs; triphenylethylene derivatives (e.g., tamoxifen) and benzothiophene derivatives (e.g., raloxifene). Tamoxifen, raloxifene and toremifene are the most widely used SERMs. Tamoxifen, an antagonist of the breast tissue, is the first clinically identified compound with noticeable SERM activity. Although tamoxifen has been very successful in breast cancer treatment, its agonistic effect on the uterus is said to be associated with increase risk of developing endometrial cancer. Ideally, it is presumed that SERMs should selectively act as an agonist in the bone and brain while simultaneously acting as an antagonist in the breast and uterus. Therefore, the therapeutic goal of SERMs is the prevention of estrogen deficiency diseases without promoting estrogen-associated tumor growth. Therefore, the objective of this review is to summarize various effects that have been applied in improving the tissue-selectivity of SERMs, highlighting the emerging understanding of their mechanism of actions in selected target tissues and the development of the SERMs. The significance in recent discovery of selective estrogen receptor alpha modulators, SERAMs will also be reviewed.