The NF-kappaB family of transcription factors regulates many genes that are essential primarily for the development, maintenance and function of the innate and adaptive immune systems. Thus, aberrant activity of the nuclear factor NF-kappaB has a role in many pathological conditions with inflammatory and autoimmune components. Estrogen receptors (ERs) are transcription factors that mediate the biological responses to the sex hormone estrogen and are essential for reproduction and for functions of the cardiovascular, skeletal and nervous systems. Recent studies have demonstrated molecular cross-talk between these families of transcription factors in which the ER mediates inhibition of NF-kappaB activity at several levels. Such cross-talk between these important regulators of the endocrine and immune systems might be exploited for the treatment of cancer and inflammatory and autoimmune diseases.