In this issue of Blood, Kabiri and coworkers report the hematopoietic deletion of the endoplasmic reticulum–localized O-acyltransferase porcupine (PORCN), which is necessary for acylation of Wnts in the endoplasmic reticulum, enabling their secretion and binding to the frizzled receptors. Unexpectedly, the absence of secreted Wnt factors does not have major effects on steady-state in vivo hematopoiesis or on long-term repopulating activity of Wnt-deficient hematopoietic stem cells.