The two transcription factors estrogen receptor α (ERα) and cyclic adenosinemonophosphate (cAMP)–responsive element binding protein 1 (CREB1) mediate different signals, bind different response elements, and control different transcriptional programs. And yet, results obtained with transfected reporter genes suggested that their activities may intersect. We demonstrate here that CREB1 stimulates and is necessary for ERα activity on a transfected reporter gene and several endogenous targets both in response to its cognate ligand estrogen and to ligand-independent activation by cAMP. The stimulatory activity of CREB1 requires its DNA binding and activation by phosphorylation, and affects the chromatin recruitment of ERα. CREB1 and ERα are biochemically associated and share hundreds to thousands of chromatin binding sites upon stimulation by estrogen and cAMP, respectively. These shared regulatory activitiesmay underlie the anti-apoptotic effects of estrogen and cAMP signaling in ERα-positive breast cancer cells. Moreover, high levels of CREB1 are associated with good prognosis in ERα-positive breast cancer patients, which may be because of its ability to promote ERα functions, thereby maintaining it as a successful therapeutic target.