Human neuroblastoma arises from the developing neural crest. Tumors are categorized clinically by their location, age at diagnosis, spread/metastasis, and degree of cellular maturation and heterogeneity. Our long-term studies have shown the presence in human neuroblastoma cell lines of three distinct cell types: I-type stem cells, N-type neuroblastic/neuroendocrine precursors, and S-type Schwannian/melanoblastic precursors. These distinct cell types can differentiate predictably along specific neural crest lineages in response to particular morphogens. As assessed by tumor formation in nude mice and anchorage-independent growth in soft agar, I-type stem cells are significantly more malignant than either N- or S-type cells. Recent research shows that three similar cell types are also present in human neuroblastoma tumors. Using immunocytochemical, laser-capture microdissection, or short-term culture methods to identify cell types in tumors of different stages and/or different outcomes, these studies have shown that (1) all tumors contain neuroblasts in various differentiation states; (2) presumptive I-type stem cells are present in tumors of all stages; and (3) stromal cells may be tumor-derived, i.e. S-type cells, as well as of normal origin. More importantly, there is a higher incidence of I-type cells in tumors that progress, consistent with the high malignant potential of this cell type in vitro. A better understanding of the cause and consequences of cellular heterogeneity of human neuroblastoma tumors is an important prerequisite to the development of more effective therapies for this often fatal disease.