Notch receptor signaling controls cell-fate specification, self-renewal, differentiation, proliferation and apoptosis throughout development and regeneration in all animal species studied to date. Its dysfunction causes several developmental defects and diseases in the adult. A key feature of Notch signaling is its remarkable cell-context dependency. In this review, we summarize the influences of the cellular context that regulate Notch activity and propose a model how the interplay between the cell-intrinsically established chromatin state and the cell-extrinsic signals that modify chromatin may select for Notch target accessibility and activation in different cellular contexts.