Medulloblastomas represent about 25% of all pediatric intracranial neoplasms. These highly malignant tumors arise from the cerebellum affecting mainly children between ages 5 and 15. Although the etiology of medulloblastomas has not yet been elucidated, several reports suggest that insulin-like growth factor I (IGF-I) may contribute to the development of these tumors. Results of this study show that the majority of cases examined were characterized by the abundant presence of the receptor for IGF-I (IGF-IR) protein (16 of 20 cases), and its major signaling molecule, insulin receptor substrate 1 (IRS-1; 15 of 20). Protein levels for IGF-IR and IRS-1, determined by Western blot and immunohistochemistry, were significantly higher in medulloblastoma biopsies than in control cerebellar tissue. By immunohistochemistry, 10 of 17 biopsies examined were also positive for the anti-pY1316 antibody staining that specifically recognizes the phosphorylated (active) form of the IGF-IR. These findings correlate with the fact that phosphorylated forms of the downstream-signaling molecules Erk-1, Erk-2, and Akt/protein kinase B were found in medulloblastoma biopsies but not in control cerebellar tissue. Importantly, there is a strong inverse correlation between biopsies that are positive for anti-pY1316 and for anti-Trk-C immunoreactivity. These observations direct our attention to the IGF-IR system as a potential therapeutic target in medulloblastomas and suggest a possibility of using the anti-pY1316 antibody as a potential prognostic marker for medulloblastomas.