Analysis of the cellular origin of carcinomas of different organs indicates that there is in each instance, a determined stem cell required for tissue renewal that is the cell of origin for carcinomas. The normal tissue-determined stem cells are the result of differentiation in the embryo and are little changed, if at all, from the embryonic cells. Malignant stem cells are derived from these normal stem cells of adult tissues. The resultant tumors are caricatures of the normal process of tissue renewal with many stem cells and imperfect differentiation (14). This imparts an undifferentiated appearance to the tumors, not a dedifferentiated one. Study of the regulation of normal stem cells in the embryo should lead to rational therapies for malignant ones, and conversely, study of secretions and regulation of malignant stem cells will provide insights into normal regulation. The cancer-derived differentiated cells are benign (12, 74) if not normal (39, 53) leading to the conclusion that attempts to direct normal differentiation of malignant stem cells might serve as an alternative to cytotoxic therapy. Attempts to develop such therapies are currently underway (208). The degree of differentiation of a carcinoma depends on the proportion of undifferentiated tumor stem cells, the stage of maturation arrest of the majority of cells in the tumor, and on the ability of some cells to escape arrest and to differentiate (Fig. 1). These concepts of the stem cell contribution to tumors originated largely from studies of teratocarcinoma (209) and were not widely accepted because many considered the lessons learned were unique to teratocarcinomas and would not apply to other tissues. On the basis of the concepts covered in this review, it is clear that teratocarcinomas are unique only in the potential of their stem cells. Other stem cells have more limited potential. The balance of expression of the differentiated histiotype of the tumor cell lineage and the undifferentiated phenotype of the tumor stem cells determine the morphology of the tumor. Normal tissue renewal of epithelial organs is also from stem cells or their differentiating progeny. The cellular events during liver development and regeneration and the changes that precede the development of liver cancer during hepatocarcinogenesis are similar to the cellular response in pancreas, prostate, breast, lung, and gut. In liver, as in the leukopoietic system, the primitive tissue-specific stem cell is not primarily involved in renewal because that would be too slow a process; individuals would die before generation of sufficient replacement cells.(ABSTRACT TRUNCATED AT 400 WORDS)