Abstract: Transgenic mammals, cells derived from the animals, and methods of using these to monitor the endoplasmic reticulum (ER) stress response are provided. In some embodiments, the methods allow for monitoring the ER stress response in real time. Some of the methods allow non-invasive in vivo visualization of ER stress response. Also provided are methods of screening molecules and/or treatment conditions for the ability to modulate the ER stress response, methods of treating diseases characterized by ER stress response activity, and methods of detecting the toxicity or therapeutic ratio of molecules that modulate the ER stress response.