The non-steroidal selective estrogen receptor modulator (SERM) tamoxifen has been used as standard first-line therapy for postmenopausal breast cancer since the 1970s, during which time over 400,000 lives have been saved. Nevertheless, much attention has been paid to the side effect profile of tamoxifen, particularly in terms of cardiovascular and endometrial abnormalities. Third generation non-steroidal aromatase inhibitors, such as anastrozole and letrozole, have been approved as an alternative, although it is still too early to judge what long-term adverse effects might be associated with prolonged restriction of the supply of estrogen. Novel SERMs have demonstrated improved characteristics over tamoxifen, reducing or eliminating certain adverse events while retaining breast tumor-reducing efficacy. Thus, these agents could provide a direct substitute for tamoxifen. In addition, other estrogen receptor (ER) subtype-selective modulators are under investigation, and the importance of ERbeta as a positive prognostic indicator may open up further therapeutic opportunities. Resistance to hormonal therapies is still a major problem and identifiying the onset of the development of resistance, together with earlier intervention with inhibitors of growth-factor driven cell survival pathways, in combination or sequentially, requires more intense study.