Erythropoiesis is principally controlled through erythropoietin (Epo)-receptor signaling, which involves activation of JAK2 and Lyn tyrosine kinase; both have important roles in regulating red blood cell development. Negative regulation of Lyn kinase activity involves Csk-mediated phosphorylation of its C-terminal tyrosine, which is facilitated by the transmembrane adaptor Csk-binding protein (Cbp). While Cbp has significant functions in controlling Lyn levels and activity in erythroid cells in vitro, its importance to primary erythroid cell development and signaling has remained unclear. To address this, we assessed the consequence of loss of Cbp on the erythroid compartment in vivo, and whether Epo-responsive cells isolated from Cbp knockout mice exhibited altered signaling. Our data show that male Cbp-/- mice display a significant alteration to late erythroid development in bone marrow with evidence of increased erythrocytes in the spleen, while female Cbp-/- mice exhibit an elevation in early erythroid progenitors (not seen in male mice) which does not influence the later steps in red blood cell development. In isolated primary erythroid cells and cell lines generated from Cbp-/- mice, survival signaling through Lyn/Akt/FoxO3 was elevated, resulting in sustained viability during differentiation. The high Akt activity disrupted GAB2/SHP-2 feedback inhibition of Lyn, however the elevated Lyn activity also increased inhibitory signaling via SHP-1 to restrict the Erk1/2 pathway. Interestingly, while the elevated Lyn activity and alterations to Epo-signaling led to changes to late red blood cell development in male Cbp-/- mice, this was not apparent in female Cbp-/- mice, and is potentially due to their elevated estrogen, which is known to facilitate early progenitor self-renewal.