During evolution of the vertebrate cardiovascular system, the vast endothelial surface area associated with branching vascular networks mandated the development of molecular processes to efficiently and specifically recruit circulating sentinel host defense cells and tissue repair cells at localized sites of inflammation/tissue injury. The forces engendered by high‐velocity blood flow commensurately required the evolution of specialized cell surface molecules capable of mediating shear‐resistant endothelial adhesive interactions, thus literally capturing relevant cells from the blood stream onto the target endothelial surface and permitting subsequent extravasation. The principal effectors of these shear‐resistant binding interactions comprise a family of C‐type lectins known as ‘selectins’ that bind discrete sialofucosylated glycans on their respective ligands. This review explains the ‘intelligent design’ of requisite reagents to convert native CD44 into the sialofucosylated glycoform known as hematopoietic cell E‐/L‐selectin ligand (HCELL), the most potent E‐selectin counter‐receptor expressed on human cells, and will describe how ex vivo glycan engineering of HCELL expression may open the ‘avenues’ for the efficient vascular delivery of cells for a variety of cell therapies.