A new view of the hematopoietic differentiation tree. (A) The traditional model: A homogeneous population of HSCs drives the hematopoietic system. This implies that all HSCs in the population will react in the same way to identical extrinsic stimuli. On commitment, each HSC generates the same number of myeloid (red) and lymphoid (blue) progenitors. Homeostatic mechanisms (curved arrows) adjust myeloid and lymphoid cells to the typical ratios seen in blood. (B) The new model: Several populations of HSCs each with distinct, stable differentiation programs drive the hematopoietic system. The thickness of the arrows corresponds to the ability of the HSCs to generate progeny of the indicated type. Straight arrows indicate that the ratios of lymphoid to myeloid precursors are reflected in the periphery. My-bi HCSs produce few lymphocytes but standard levels of myeloid cells. The reverse is true for Ly-bi HSCs; they generate few myeloid cells but standard levels of lymphocytes. Bala HCSs generate more lymphocytes than myeloid cells (at least in mouse) and are called balanced because their output resembles the average output of mature cells from all HSC subsets together. All HSCs have self-renewal capacity (yellow arrow), and all HSCs give rise to all types of mature cells and thus are true multipotent stem cells.