The aim of this study was to identify molecules involved in the proliferation and survival of recurrent estrogen receptor (ER)-positive breast cancer at the site of metastasis. Most studies of biomarkers are done using the initial primary breast tumor whereas pathological studies of breast cancer lesions after distant recurrence are scarce. Here we evaluated the expression of the oncogenes c-Myc and Bcl-2, mediators of estrogen-dependent proliferation and survival, during breast cancer progression and relapse after adjuvant hormonal therapy. Using a preclinical model of tamoxifen-resistant growth, we found overexpression of c-Myc in all (3/3) and of Bcl-2 in most (2/3) tamoxifen resistant-breast cancer variants. To determine whether c-Myc and Bcl-2 are expressed during breast cancer progression in the clinics we identified breast cancer patients who had received adjuvant hormonal therapy for the treatment of their localized disease and had later experienced relapse. From 583 patients who had received adjuvant hormonal therapy a total of 82 experienced recurrence. Nevertheless, only 22 patients had had a biopsy of their metastatic lesion done after relapse. Twenty-one biopsies were useful for this biomarker study. These biopsies were obtained mostly (20) from breast cancer patients who had received tamoxifen as their adjuvant hormonal therapy. One patient had received an aromatase inhibitor instead. Our results showed that almost all (20) metastatic recurrences expressed ER. Expression of c-Myc was observed in 18 out of 19 metastatic lesions scored while expression of Bcl-2 was detected in 17 out of 21 metastatic tumors. A correlation between ER expression and Bcl-2, but not with c-Myc, was found in these recurrent metastatic lesions. In addition, c-Myc expression was correlated with the nuclear grade of the metastatic lesion. Thus, the frequent expression of c-Myc and Bcl-2 in metastatic breast cancer recurrences suggests that combining hormonal therapy with strategies to block c-Myc and Bcl-2 may prevent growth of ER-positive breast cancer at the site of metastasis.