The transcriptional coactivator Cbp plays an important role in a wide range of cellular processes, including proliferation, differentiation, and apoptosis. Although studies have shown its requirement for hematopoietic stem cell (HSC) development, its role in adult HSC maintenance, as well as the cellular and molecular mechanisms underlying Cbp function, is not clear. Here, we demonstrate a gradual loss of phenotypic HSCs and differentiation defects following conditional ablation of Cbp during adult homeostasis. In addition, Cbp-deficient HSCs reconstituted hematopoiesis with lower efficiency than their wild-type counterparts, and this response was readily exhausted under replicative stress. This phenotype relates to an alteration in cellular fate decisions for HSCs, with Cbp loss leading to an increase in differentiation, quiescence, and apoptosis. Genome-wide analyses of Cbp occupancy and differential gene expression upon Cbp deletion identified HSC-specific genes regulated by Cbp, providing a molecular basis for the phenotype. Finally, Cbp binding significantly overlapped at genes combinatorially bound by 7 major hematopoietic transcriptional regulators, linking Cbp to a critical HSC transcriptional regulatory network. Our data demonstrate that Cbp plays a role in adult HSC homeostasis by maintaining the balance between different HSC fate decisions, and our findings identify a putative HSC-specific transcriptional network coordinated by Cbp.