The endoplasmic reticulum (ER) chaperone BiP binds unfolded proteins to prevent their aggregation and is upregulated following activation of the ER unfolded protein response. BiP ADP ribosylation has been suggested to contribute to the fast adaptation of the ER to the changing levels of unfolded proteins. Consistent with this, Chambers et al. report that BiP ADP ribosylation that is observed in the pancreas of fasted mice (low protein synthesis) is reversed following feeding (high protein synthesis). Moreover, they identify the conserved Arg470 and Arg492 residues as sites for ADP ribosylation in BiP. Interestingly, this modification alters the electrostatic properties of BiP, and mutations that mimic the charge changes induced by ADP ribosylation destabilize BiP–substrate binding. Finally, kinetic studies suggested that BiP ADP ribosylation, which correlates with low levels of newly synthesized proteins, allows protein folding, whereas BiP deribosylation during increased protein synthesis prevents aggregation of unfolded proteins.