Understanding the molecular mechanisms controlling normal hematopoietic differentiation is critical to develop new treatments for blood diseases and to manipulate stem cells. Despite the identification of many players in hematopoiesis, the molecular mechanisms controlling hematopoietic differentiation remain poorly understood. Due to a number of recent findings, the targeting of regulators of hematopoiesis to proteasomal degradation might be an important step in control of this developmental program.