Members of the fibroblast growth factor (FGF) family, which normally control cerebellar neuronal maturation, may represent more natural and less toxic tools with which to target medulloblastoma (MB), an embryonal brain tumor thought to arise from cerebellar neuronal precursors. In support of this, we found previously basic FGF/FGF-2 can inhibit MB progression by inducing neuronal-like differentiation, slowing the growth, and triggering apoptosis of a MB cell line we established from a histopathologically classic tumor (R. L. Kenigsberg et al., Am. J. Pathol., 151: 867-881, 1997). In the present study, the usefulness of this approach is additionally investigated. We report that of the five FGFs found in the developing cerebellum, only two, FGF-2 and FGF-9, possess antitumoral activity for MB. This activity is only noted for cell lines that originate from classic (UM-MB1 and SYR) rather than desmoplastic (HSJ) tumors. Whereas these FGFs inhibit proliferation of both classic cell lines, they only advance neuronal differentiation and induce apoptosis of one, UM-MB1. Consistent with these responses, after FGF treatment, levels of neurofilaments and the proapoptotic modulator Bax only increase in UM-MB1, whereas the cyclin-dependent kinase inhibitor p27/Kip1 (p27), which accumulates in cerebellar neuronal precursors before they exit the cell cycle, goes up in both UM-MB1 and SYR. Finally, although the histological variant of MB may help predict the sensitivity of MB to the FGFs, the selectivity, specificity, and type of response elicited may be dictated by, as evident by immunoprecipitation and Western blot analyses, the expression of certain FGF receptor types.