In this issue of Blood, Liu and colleagues demonstrate that active endoplasmic reticulum associated degradation (ERAD) of misfolded proteins is required to maintain hematopoietic stem cell (HSC) quiescence, and hence proper long-term blood formation 1. They identify a mechanism by which the Sel1L protein, a key member of the ERAD complex, maintains HSCs in a state of low mTORC1 activity, thereby preventing HSC proliferation. This data implicate that steady-state protein quality control directly contributes to keeping HSCs outside of the cell cycle.