 Abstract cells must rapidly respond and efficiently adapt to environmental changes. Yeast cells have multiple pathways that respond to specific environmental insults, as well as a general stress response program regulated by two transcription factors, MSN2 and MSN4. These factors integrate information from upstream pathways to produce a fast, tunable, and robust response to different environmental changes. Using a systematic approach, researchers identified numerous genetic and epistatic interactions between different components in the network upstream to MSN2 or 4. This analysis gained new insights into the functional specialisation of the IAS paralogs in the repression of stress response and identified a three-way cross-talk between the mediator complex, the Hobmak pathway, and the Kamp PKA pathway. This article was authored by Genia Gutin, Amit Sader, Ayelet Rahat, and others.