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All cells must actively monitor and regulate the output of their organelles to sustain a healthy life and adapt to changing environmental and developmental needs. Using a wide variety of genetic, cell biological, and biophysical approaches, we aim to understand the molecular mechanisms by which organelles are built, how proteins are targeted to them, how they communicate, and how they are maintained in proper abundance. Imbalances in the endoplasmic reticulum, for example, induce the unfolded protein response (UPR), an intracellular signaling network that we study in yeast and mammalian cells. We explore the mechanisms by which the UPR reestablishes homeostasis or switches into apoptotic programs, both in health and disease.