The inducible, higher eukaryotic transcription factor NF‐kappa B is activated by a variety of external stimuli including inflammatory cytokines, viral and bacterial infection and UV irradiation. Here we show that internal stress, caused by the accumulation of proteins in the endoplasmic reticulum (ER), also induces NF‐kappa B DNA binding as well as kappa B‐dependent gene expression. This was observed upon expression of immunoglobulin mu chains in the absence of light chains and by treatment of cells with several agents known to cause ER stress, such as tunicamycin, brefeldin A, 2‐deoxyglucose and thapsigsargin. The transcription factor AP‐1 was weakly induced under similar conditions. Overexpression of NF‐kappa B subunits did not influence expression of the gene encoding grp78/BiP, a protein induced by various forms of ER stress. Likewise, the glucosidase inhibitor castanospermine, which induced grp78/BiP expression, failed to activate NF‐kappa B, while the antioxidant dithiothreitol augmented grp78/BiP expression but prevented activation of NF‐kappa B. Hence, NF‐kappa B participates in a novel ER‐nuclear signal transduction pathway distinct from the unfolded‐protein‐response described previously. We provide evidence that the ER can produce at least two distinct signals in response to a functional impairment. One is emitted by the presence of unfolded proteins, the other in response to overloading of the organelle, for example through the overexpression of secretory proteins.