The signaling pathways that are critical to the development and growth of breast cancer include those activated downstream of the estrogen receptor (ER) and the human epidermal growth factor receptor family. Many of these pathways, including the signal transducer and activator of transcription pathway, are common to both. The well-described genomic actions of ER involve its role as a transcription factor, either by binding directly to DNA through estrogen response elements, or by tethering to DNA through interaction with other proteins. Nongenomic signaling by the ER involves interaction with membrane-associated signaling proteins such as the c-Src tyrosine kinase and adapter proteins p130Cas and moderator of nongenomic activity of ER. Interactions with the signal transducer and activator of transcription pathway are important in both ER signaling pathways and are critical for estrogen-induced proliferation and tumorigenesis. These mechanisms of signaling cross talk and their role in resistance to antiestrogen therapies are discussed.