Currently, hematopoietic stem cells derived from the bone marrow or from cord blood are used to treat patients who require hematopoietic stem cell treatment. In spite of the varied sources from which hematopoietic stem cells may be obtained, there is still shortage of genetically matched hematopoietic stem cell grafts. As a result, many patients requiring transplantation cannot benefit from the procedure. Efforts have been made in time past to expand this unique type of adult stem cells in culture, with little success. These stem cells, even in the presence of several exogenous cytokines, serum factors and support from (mesenchymal) cells do not propagate the stem cells beyond a few days. However, reports from recent studies indicate that long-term propagation and large-scale expansion of hematopoietic stem cells is now possible with the use of endothelial cells in co-culture with hematopoietic stem cells. These studies have demonstrated that the presence of endothelial cells is necessary for promoting self-renewal of Hematopoietic Stem Cells (HSC), for long-term survival of repopulating HSCs and for increasing the number of these cells in culture. Endothelial cells from blood vessels constitute the basic building blocks of the human vasculature, being a key constituent of the bone marrow and vascular niche that support hematopoietic mobilization, maintenance and regeneration. Researchers have not only found that endothelial cells could greatly expand HSCs but the proliferation induced by endothelial cells carries no risk of tumor formation. There is a dire need to translate this revolutionary finding from the laboratory into routine clinical use. The purpose of this review therefore, is to glean the several studies related to the subject into a practical protocol scalable for clinical application.