Studies from our and other laboratories have over the last 2 years implicated the existence of multipotent progenitors (MPPs) with combined granulocyte-macrophage, B cell, and T cell potential, but little or no megakaryocyte-erythroid (MkE) potential in the adult bone marrow Lineage(-)SCA-1(+)KIT(+) (LSK) compartment of multipotent stem and progenitor cells. The evidence for the existence of LSKCD34(+)FLT3(hi) lymphoid-primed MPPs (LMPPs) implicates that a strict separation into common myeloid and lymphoid pathways might not be the first lineage commitment step of hematopoietic stem cells (HSCs). Together with the evidence for existence of common myeloid and common lymphoid progenitors (CMPs and CLPs, respectively), the identification of LMPPs also suggests that at least the granulocyte-macrophage lineage can be generated through alternative pathways. However, the existence of LMPPs has recently been questioned, as there is evidence that at least a fraction of LSKCD34(+)FLT3(hi) cells sustains MkE potential. Thus, in more recent studies we have in more detail compared the molecular signature of adult LMPPs to populations of LSK cells enriched for cells with pluripotent HSC activity. Notably, we have found at the global as well as single-cell level that LMPPs when compared with pluripotent HSCs downregulate the transcriptional priming of genes typically expressed in cells of the MkE lineage, while upregulating early lymphoid genes. Although other studies have suggested that the earliest HSC commitment steps might differ in fetal and adult hematopoiesis, we have also obtained evidence suggesting that the LMPP is defined already during fetal development.