More than 30 yr ago, a collection of cells isolated from the bone marrow were first demonstrated to repopulate hematopoiesis in a radioablated animal. These cells self-renewed while producing all of the blood products and were named hematopoietic stem cells (HSCs). Since then, HSCs have been a tremendous boon to both basic science in understanding cell biology and as therapy in a cancer transplant setting. More recent work has shown that the HSCs, and possibly populations of cells residing in other tissues, have the properties of stem cells and the ability to repopulate nonrelated organs and tissues. This promiscuous repopulation has been termed plasticity and is the center of much research and even more debate. Our laboratory has recently proven that the HSCs meet the requirements of a stem cell by self-renewing and producing all of the blood lineages while concurrently demonstrating their ability to produce nonhematopoietic endothelial cells of blood vessels. This plasticity of the HSCs demonstrates hemangioblast activity, proven by both single cell and serial HSC transplants, and is the focus of this chapter.