The renewal of normal epithelia depends on a small sub-population of cells, termed somatic stem cells, whose primary characteristic is an ability for indefinite self-renewal. Evidence is accumulating that the growth of tumours similarly depends on a sub-population of malignant stem cells, often termed tumour-initiating cells. Tumour-initiating sub-populations within solid tumours have been identified by their cell surface expression of various phenotypic markers and by their ability to regenerate tumours in immune-deficient mice. Cells with such clonogenic abilities differ consistently from the remainder of the cell population in cellular properties such as size, adhesiveness, dye exclusion, and patterns of gene expression. Sub-populations of malignant cells freshly isolated from tumours also show differing patterns of expression of molecules related to stem cell maintenance and asymmetric division. As the cells ultimately responsible for tumour renewal, malignant stem cells appear to form the necessary target of therapy but some findings indicate greater resistance of these cells to the induction of apoptotic cell death and their potential failure to respond effectively to standard therapeutic procedures. Of particular interest, cells with clonogenic properties and expression patterns similar to those of tumour-initiating cells in vivo persist in malignant cell lines and show similar apoptotic resistance. Cell lines may thus provide a model for analysis of malignant stem cell properties and may be useful for the development of appropriate methods for their elimination.