During the development of blood vessels in the embryo some of the blood vessel lining cells, called hemogenic endothelial cells, become blood stem cells, which then create the circulating blood system that exists for the entire life of an individual. Although we have learned a lot about what signals drive some endothelial cells to become blood cells, much less is known about how other cells in the embryo regulate this process to ensure adequate blood production over a lifetime. The programs that are activated to make blood stem cells is key to understanding how endothelial cells choose their fate. We have identified a gene called Sash1 that sends signals from different cell types to promote the endothelial cells to make blood stem cells, and we are now elucidating the mechanisms of this process using spatial profiling, single cell sequencing and functional studies. Blood stem cell transplantation is critical for adults with leukemia and other cancers to be able to replenish a normal blood system after treatment with chemotherapy or radiotherapy. Recently there has been some progress in making new blood stem cells in a dish, and our work will help improve these methods. Understanding what signals coax the endothelial cells to become blood stem cells, and what other cell types are required for this process is critical in understanding mechanisms of blood stem cell formation and improving treatments for blood and other cancers.