The receptor for the female hormone progesterone (PR), like that for estrogen (ER), is an important predictive marker for response to endocrine therapy in patients with breast cancer. PR exists as two isoforms, A and B. PR is important in mammary gland development and excess production of PRB is associated with breast cancer risk. Overabundance of PRA is related to resistance to tamoxifen. Total loss of PR is linked to reduced benefit from tamoxifen in both the adjuvant and metastatic settings. The predictive significance of PR expression was originally explained on the basis that PR is an ER-regulated gene and its presence indicates a functioning ER pathway and, therefore, an endocrine-responsive tumor. More recent data, however, suggest an alternative explanation. While many studies show that loss of PR predicts relative resistance to the antiestrogen tamoxifen, a recent study suggests that PR loss may not indicate resistance to aromatase inhibition. The finding that PR loss may not correlate with resistance to aromatase inhibition may be related to crosstalk between ER and PR and growth factor receptor pathways such as HER2. PR loss in some tumors is due to excessive growth factor receptor signaling (overexpression of HER2), which downregulates expression of the PR gene. Neoadjuvant studies also show that HER2 signaling is associated with tamoxifen resistance, but not resistance to aromatase inhibitors. Therefore, high HER2 signaling could explain both PR loss and resistance to tamoxifen while the response to aromatase inhibitors is maintained. In this way, PR loss in some tumors may be a surrogate marker for increased signaling through the growth factor receptor tyrosine kinase pathway and it may help clinicians decide between initial use of an aromatase inhibitor or tamoxifen in the individual patient.