Tal1, which encodes a helix-loop-helix transcription factor, is thought to be a master gene of hematopoiesis, because Tal1-deficient mice are blood-less and the embryonic stem (ES) cells do not give rise to any hematopoietic cell lineage without Tal-1. We recently reported that exogenous expression of an ets-family transcription factor, PU.1, rescues the development of macrophage and osteoclast lineages, but not of erythrocyte, megakaryocyte, mast cell, or B lymphocyte lineages from Tal-1-deficient ES cells. Since PU.1 is not detected in differentiating ES cells lacking Tal1 and the development of macrophages and osteoclasts was rescued by compensated expression of PU.1, our results strongly suggest that Tal-1 plays a key role in hematopoiesis as a molecule essential for the expression of lineage-affiliated genes during blood cell differentiation. These findings lead to a new concept of the relationship between Tal-1 and lineage-affiliated transcription factors in hematopoiesis, and suggest a means to control the differentiation of HSCs into only specific lineage(s) of cells that we desire.