During mammalian development, as exemplified by mice, hematopoietic cells first appear in the yolk sac blood islands, then in the dorsal aorta of the aorta-gonad-mesonephros (AGM) region and the placenta, eventually seeding into liver, spleen and then bone marrow. The formation of hematopoietic stem cells from mesodermal precursors has finished by mid-fetal life. Once established, the hematopoietic system must supply blood cells to host circulation and tissues for the entire life of the animal. Easy access to hematopoietic cells has enabled a vast number of studies over the last several decades, and much is now understood about the different hematopoietic lineages, how they differentiate, and their derivation from immature progenitors. Yet to be elucidated are the following two intriguing questions: do yolk sac and AGM hematopoietic cells arise from a common precursor or from distinct precursor cells?; and what is the lineage relationship between blood and endothelial cells. In this review, we will survey the state of our current knowledge in these areas, and discuss the potential use of multicolor chimera analyses to elucidate unresolved questions.