During the past 20 years, the hormonal therapy of choice for the treatment of breast cancer has been the antiestrogen, tamoxifen. The use of tamoxifen has been proved to produce a favorable response and survival advantage in patients whose tumors are classified as estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+). Additionally, tamoxifen is the only drug known to reduce the incidence of contralateral disease. This drug produces relatively few harmful side effects, while exhibiting several beneficial effects such as maintaining bone density and reducing the incidence of myocardial infarction in the postmenopausal woman. However, tumors eventually acquire a tamoxifen-resistant or tamoxifen-stimulated phenotype, resulting in disease recurrence. Several mechanisms have been proposed to account for tamoxifen-resistant breast cancer, in the hope of developing a more effective first-line or perhaps second-line treatment strategy. One popular theory is the occurrence of a mutation in the estrogen receptor, the drug target. A plethora of studies have reported the detection of estrogen receptor mRNA splice variants, and it has been suggested that the accumulation of these variant mRNAs are responsible for the development of tamoxifen-resistant breast cancer. In this review, several questions will be posed to address the suitability of both laboratory and clinical evidence to support this hypothesis. Although there is adequate data generated in the laboratory, there is, as yet, no compelling evidence to suggest that mutation of the estrogen receptor is the molecular mechanism producing tamoxifen-stimulated growth in human breast and endometrial cancer.