Human neuroblastoma (NB) is a highly malignant tumor arising in cells that originate in the embryonal neural crest. Several lines of investigation suggest that both NB and other tumors of developing tissues are blocked in their ability to differentiate and achieve growth arrest. Since in vivo differentiation of NB has been frequently observed and may be of clinical importance (Fox et al., 1959; Evans et al., 1976), we have utilized the in vitro induction of NB differentiation by retinoic acid (RA) to study the molecular events associated with NB differentiation. We have focused our studies on changes that occur in the expression of various proto-oncogenes during NB tumors cell differentiation because proto-oncogenes are likely to be of central importance in mediating processes critical for cellular growth and maturation. In these studies, we have found that the expression of no fewer than five proto-oncogenes including c-Ha-ras, c-ets-1, and c-fos change during the differentiation of NB cells, while the expression of c-erb-B changes in association with the arrest of growth that occurs during NB differentiation. In some cases the altered expression of a proto-oncogene was transcriptionally regulated, while in others post-transcriptional mechanisms were important.