The Hematopoietic stem cell (HSC) continuously regenerates the hematologic system, yet few genes regulating this process have been defined. To elucidate factors involved in differentiation and self-renewal, we have generated the first in-depth expression database of hematopoietic stem cells and their differentiated progeny, including erythrocytes, granulocytes, monocytes, NK cells, activated and naive T-cells, and B-cells. Bioinformatic analysis revealed HSC were more transcriptionally active than their progeny and shared a common activation mechanism with T-cells. Each cell type also displayed unique biases in the regulation of particular genetic pathways, with Wnt signaling particularly enhanced in HSCs. We identified ~100 to 400 genes uniquely expressed in each cell type, termed lineage fingerprints. In overexpression studies, two of these genes, Zfp105 from the NK cell lineage, and Ets2 from the monocyte lineage, were able to significantly influence differentiation toward their respective lineages, demonstrating the utility of these fingerprint genes for controlling differentiation of stem and progenitor cells.