Extracellular signal-regulated kinase 1 (Erk1) and Erk2 play crucial roles in cell survival, proliferation, cell adhesion, migration, and differentiation in many tissues. Here, we report that the absence of Erk1 and Erk2 in murine hematopoietic cells leads to bone marrow aplasia, leukopenia, anemia, and early lethality. Mice doubly-deficient in Erk1 and Erk2 show rapid attrition of hematopoietic stem cells and immature progenitors in a cell-autonomous manner. Reconstitution studies show that Erk1 and Erk2 play redundant and kinase-dependent functions in hematopoietic progenitor cells. Moreover, in cells transformed by the oncogenic KRas^G12D allele, the presence of either Erk1 or Erk2 with intact kinase activity is sufficient to promote cytokine-independent proliferation.