Endoplasmic reticulum (ER) to mitochondria communication has emerged in recent years as a signaling hub regulating cellular physiology with a relevant contribution to diseases including cancer and neurodegeneration. This functional integration is exerted through discrete interorganelle structures known as mitochondria-associated membranes (MAMs). At these domains, ER/mitochondria physically associate to dynamically adjust metabolic demands and the response to stress stimuli. Here, we provide a focused overview of how the ER shapes the function of the mitochondria, giving a special emphasis to the significance of local signaling of the unfolded protein response at MAMs. The implications to cell fate control and the progression of cancer are also discussed.