Endoplasmic reticulum (ER) stress induces an adaptive program called the unfolded protein response (UPR), which affects activity of an array of kinases and transcription factors. Previous reports provided evidence for activation of nuclear factor-kappaB (NF-kappaB), the major transcription factor regulating inflammatory processes, by ER stress. However, recent investigation also suggested that preceding ER stress suppresses activation of NF-kappaB by subsequent exposure to inflammatory stimuli. Although ER stress induces activation of NF-kappaB in the early phase, consequent UPR may inhibit NF-kappaB-dependent cellular activation in the later phase. This article summarizes current knowledge on potential mechanisms underlying the biphasic, bidirectional regulation of NF-kappaB by ER stress.