The membrane-bound transcription factor ATF6 alpha plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6 alpha promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6 alpha signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6 alpha signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6 beta or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6 alpha and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination.