Interactions between the estrogen receptor (ER) and the epidermal growth factor receptor (EGFR) contribute to the biological effects of these binding protein families. EGFR stimulates DNA synthesis and gene transcription in the uterus, related in part to estrogen-independent activation of the nuclear ER. This results from signal transduction enacted by the plasma membrane tyrosine kinase growth factor receptor, leading to 1) phosphorylation and activation of the nuclear ER, and 2) phosphorylation of coregulator proteins. More recently, it has been shown that a pool of ERalpha resides in or associates with the plasma membrane as a cytoplasmic protein. These ERs utilize the membrane EGFR to rapidly signal through various kinase cascades that influence both transcriptional and nontranscriptional actions of estrogen in breast cancer cells. This is congruent with a general theme of receptor signaling, where membrane G protein-coupled receptors activate tyrosine kinase growth factor receptors (EGFR, IGF-I receptor) that subsequently signal to MAPKs and other pathways. Overall, the bidirectional cross-talk between EGFR and cellular pools of ER contributes to reproductive organ physiology and pathophysiology.