Sequence analysis of the human genome reveals the existence of a number of potential G-protein coupled receptors whose function(s) have yet to be determined. Signalling from a wide array of G- protein coupled receptors is known to be mediated by the heterotrimeric G-protein subtype Gi. By using genetic approach we are probing the role of Gi-coupled G-protein coupled receptors in hematopiesis and determining which receptors are involved. Pertussis toxin is known to inhibit Gi signalling in mammalian cells, thus this molecule is a useful tool to explore functions of new Gi-coupled receptors, as well as new functions of known receptors: A transgenic mouse has been generated which expresses pertussis toxin conditionally within the cell. Expression of pertussis toxin in hematopoietic cells results in neonatal lethality, where the animals do not survive to weaning age. This is correlated with lung infection and perhaps defects in other hematopoietic lineages given that the bone marrow of these mice appears acellular compared to littermate controls. Furthermore, bone marrow transplantation of fetal liver cells from pertussis toxin expressing mice into lethally irradiated wild type recipients display a defect in long-term reconstitution suggesting the hematopoietic stem cells are unable to engraft. Thus, Gi-coupled receptors are necessary for hematopoiesis. At this point, G-protein coupled receptor candidates mediating this essential signalling in hematopoiesis are being identified.