CD133 antigen (prominin-1) is a useful cell surface marker of very small embryonic-like stem cells (VSELs). Antibodies against it, conjugated to paramagnetic beads or fluorochromes, are thus powerful biological tools for their isolation from human umbilical cord blood, mobilized peripheral blood, and bone marrow. VSELs are described with the following characteristics: (1) are slightly smaller than red blood cells; (2) display a distinct morphology, typified by a high nuclear/cytoplasmic ratio and an unorganized euchromatin; (3) become mobilized during stress situations into peripheral blood; (4) are enriched in the CD133(+)Lin(-)CD45(-) cell fraction in humans; and (5) express markers of pluripotent stem cells (e.g., Oct-4, Nanog, and stage-specific embryonic antigen-4). The most recent in vivo data from our and other laboratories demonstrated that human VSELs exhibit some characteristics of long-term repopulating hematopoietic stem cells and are at the top of the hierarchy in the mesenchymal lineage. However, still more labor is needed to characterize better at a molecular level these rare cells.