Progenitor/stem cells were indicated as a promising target for the treatment of different diseases, including various cancers. Progenitor cells were also tested as a potential alternative for the organ transplantation in patients with different tissue degeneration. Numerous investigations delivered a list of reliable stem cell markers, although a search for the best progenitor cell markers continues. We previously assessed breast cancer cell-line-derived mammospheres enriched in cells with a CD44+/CD24- surface profile (defined as breast cancer stem cells (BCSC)). We confirmed that BCSC express key sphingolipid signalling effectors, pro-oncogenic sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate receptor 3 (S1P3) [1]. Notably, S1P was also shown to promote homing and engraftment of CXCR4+ hematopoietic stem/progenitor cells to bone marrow stem cell niches. Progenitor cells may be used for re-population of dying and/or pathological tissues, including various pathological conditions of the liver. The transfusion of liver stem cells represents a very desirable alternative, although several limitations and complications were reported. Furthermore, the expression of the major sphingolipid effectors and their role in liver stem cell survival during transfusion and homing remain largely unclear. The role and expression of SphK/S1P receptors in disease-affected hepatocytes and liver cancer stem cells remain under-addressed. We discuss the current advances, problems, and barriers for extraction and assessment of liver stem cells. Current progress in the clinical and in vivo attempts to transplant liver stem cells is critically evaluated.