Abstract: Stem cell proliferation is tightly regulated in developing and adult tissues through the coordinated action of cell-intrinsic and extracellular signals. Although many extracellular cues were identified, the cell-intrinsic mechanisms underlying the decision of a stem cell to proliferate, enter a dormant quiescent state or differentiate into a specific cell type remains incompletely understood. Several previous studies have shown that the leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1) transmembrane protein is a tumor suppressor and a stem cell marker. Lrig1 is critically implicated in the cell-autonomous control of stem cell proliferation and/or quiescence in several tissues, including the epidermis, intestine, corneal epithelium, hard palate of the oral mucosa and brain (Herdenberg and Hedman, 2023). In most of these studies, Lrig1 controls adult tissue homeostasis by regulating proliferation and/or quiescence in different stem cell compartments. Thus, Lrig1 regulates proliferation by inhibiting epidermal growth factor (EGF) receptor (EGFR) signaling in highly proliferative stem cells. However, Lrig1 has also been reported as a signature molecule of diverse quiescent stem cell populations, including epidermal and intestinal stem cells. Although it is widely accepted that in these cell populations, Lrig1 induces quiescence by reducing EGFR activation, it has also been recently proposed that Lrig1 might regulate quiescence by enhancing bone morphogenetic protein (BMP) signaling, a well-known effector of stem cell-cycle exit and quiescence (Herdenberg et al., 2021). In relation to this, genetic ablation of Lrig1 in glioblastoma stem cells (GSCs) results in higher proliferation in response to EGFR and simultaneous poor signaling response to BMP that may underlie their lack of response to quiescence in vivo (Ferguson et al., 2022). Likewise, to normal adult neural stem cells (NSCs), GSCs can likely adopt a dynamic range of cellular states from quiescence to active proliferation. This feature enables GSCs to evade anti-mitotic therapies and lead to tumor recurrence through their reversible cellcycle arrest. Therefore, targeting Lrig1 to balance the proportion of quiescent and proliferative subpopulations of GSCs could contribute to the design of successful therapies to suppress tumor re-growth.