The ability to activate dormant transcription factors is an important molecular feature of the transcriptional regulatory networks that govern diverse cellular functions. An intriguing example is the controlled proteolytic activation of membrane-bound transcription factors (MTFs). Most MTFs are activated either by intramembrane proteases or by the ubiquitin-proteasome pathway. Recent studies have shown that several members of the bZIP and NAC families in Arabidopsis are membrane-associated and are activated by membrane-associated proteases during stress responses in the endoplasmic reticulum and when the plants experience environmental stresses. A genome-scale analysis shows that over 10% of all transcription factors are membrane bound, indicating that activation of MTFs occurs at the genomic level, allowing transcription to be regulated rapidly under stressful conditions.