Various conditions that perturb the function of the endoplasmic reticulum (ER) were recently shown to activate the transcription factor NF-kappa B. Activation of NF-kappa B is caused by the accumulation of proteins in the ER membrane, a condition we have called ER overload. Both the release of Ca2+ from the ER and the subsequent production of reactive oxygen intermediates are required for ER-overload-mediated NF-kappa B activation. This novel intracellular signal transduction pathway might be important in antiviral defense and play a role in various diseases as well as in B-cell development.