The CD34 antigen is the classical indicator molecule of pluripotent hematopoietic stem cells. But there is more and more evidence that progenitors of a yet uncommitted stem cell population do not express this surrogate marker. The bone marrow and other sites of hematopoiesis consist also of fibroblast-like stromal cells, quiescent hematopoietic stem cells, and mesenchymal stem cells. Depending on their stage of differentiation, CD34^- stem cells cannot only generate hematopoietic progenitors, but also more specified mesenchymal precursors, such as osteoblasts, chondrocytes, myocytes, adipocyts, and others. The stromal cell compartment produces not only matrix proteins, such as collagens, fibronectin and others, but also the essential growth factors, which initiate and support the differentiation of primary quiescent, but eventually activated CD34^- stem cells into CD34⁺ hematopoietic progenitors. In vivo studies have shown that long-term hematopoietic and mesenchymal reconstitution can be achieved with CD34^- stem cell lines, isolated from various sources, although the frequency of CD34^- stem cells seams to be quite low among the progenitor population. Some authors deny the reconstitution ability of CD34^- cells. The majority of CD34^- stem cells are quiescent fibroblast-like cells, which can be identified in the bone marrow biopsy as "bone lining cells". Some of those bone lining cells show protein synthesis and contain secretory vesicles. Recent studies have demonstrated that there is a surprising plasticity of the earliest stem cell population, consisting of cells with stromal cell function as well as hematopoietic and mesenchymal progenitors. The new insights into the biology of totipotent stem cells give us novel perspectives for cell- and gene therapy of various malignant and nonmalignant diseases and the possibility to replace defective organ functions with autologous CD34^- stem cells.