Human development can withstand many mutational or environmental insults. Key to robust cell fate specification are signaling pathways that detect various stresses, such as nutrient limitation, oxidative damage, or toxin exposure, and in turn instigate reactions that either alleviate or bypass such conditions. How stress responses safeguard tissue formation and homeostasis is still poorly understood. We have recently discovered several stress responses with important roles in cell differentiation, including dimerization quality control, aggregate clearance, or the reductive stress response. These pathways ensure cell homeostasis by controlling processes as diverse as complex formation, protein aggregation, and mitochondrial activity. However, while transient stress signaling provides cells with time to repair damage, these pathways must also be turned off at the right time and place. How stress response pathways are terminated is not known. Here, I will describe our discovery of a large E3 ligase, the SIFI complex, with inactivates mitochondrial stress signaling to ensure cellular homeostasis. Mutations in SIFI subunits cause neurodegenerative disease, indicating that stress response silencing is an important process to ensure tissue homeostasis.