Long-lived quiescent mammary stem cells (MaSCs) are presumed to coordinate the dramatic expansion of ductal epithelium that occurs through the different phases of postnatal development, but little is known about the molecular regulators that underpin their activation. We show that ablation of the transcription factor Foxp1 in the mammary gland profoundly impairs ductal morphogenesis, resulting in a rudimentary tree throughout life. Foxp1-deficient glands were highly enriched for quiescent Tspan8hi MaSCs, which failed to become activated even in competitive transplantation assays, thus highlighting a cell-intrinsic defect. Foxp1 deletion also resulted in aberrant expression of basal genes in luminal cells, inferring a role in cell-fate decisions. Notably, Foxp1 was uncovered as a direct repressor of Tspan8 in basal cells, and deletion of Tspan8 rescued the defects in ductal morphogenesis elicited by Foxp1 loss. Thus, a single transcriptional regulator Foxp1 can control the exit of MaSCs from dormancy to orchestrate differentiation and development. Display omitted •Foxp1 is an essential transcription factor for mammary gland development•Foxp1 controls the activation of quiescent MaSCs marked by Tspan8•Foxp1 directly represses the transcription of Tspan8 in basal, but not luminal, cells•Tspan8 deletion rescues the Foxp1-deficient mammary phenotype Fu et al. show that the transcriptional repressor Foxp1 is crucial for governing the exit of mammary stem cells from quiescence. Moreover, Tspan8 was identified as a direct Foxp1 target that plays a functional role in regulating the stem cell state, and its deletion reversed the effects of Foxp1 loss.