Medulloblastoma is the most common brain tumor in children and one third of the patients remain incurable. Tumor metastasis is one of the primary reasons for its high mortality rate. Despite evidence of overexpression of PDGFRα and PDGFRβ in metastatic medulloblastoma, their individual roles remain controversial and equivocal. Analysis of their specific signaling pathway in medulloblastoma cells revealed that PDGFRα and PDGFRβ signaling events lead to distinct cellular functions: while PDGFRβ stimulated cell proliferation and invasion, the expression of CD44 to regulate progression via c-Myc and inhibited cell death, PDGFRα displayed the opposite effects. Studies also revealed that c-Myc plays an intermediary role by regulating the downstream molecules in PDGFRβ signal pathway such as CD44 and NFB. NFB activity was found to be down- regulated in the absence of PDGFRβ pathway, with its activity restored by the overexpression of c-Myc. Analysis of medulloblastoma patient tissues without a prior knowledge of their metastatic nature further confirmed that PDGFRβ-CD44 axis regulate medulloblastoma metastasis. Co-inhibition studies performed by simultaneous inhibition of both PDGFRβ and c-Myc either by using siRNAs or by using pharmacological inhibitors demonstrated an enhanced inhibitory effect on medulloblastoma cell proliferation and migration. Using miRNA profiling of Daoy cells lacking either PDGFRβ or c-Myc alone or both, a set of miRNAs regulated by both PDGFRβ and c-Myc in common were identified. Integrative analysis of these miRNAs and their targets revealed that activation of PDGFRβ signaling and overexpression of c-Myc may enhance medulloblastoma progression via modulating the expression of several miRNAs such as miR-1280, -1260 and consequently regulating the expression of oncogenic molecules, such as Jagged 2 and CDC25A, respectively. Specific inhibition of miRNAs, miR-1280 and -1260, and JAG2 demonstrated their vital roles in medulloblastoma cell proliferation and migration. These findings suggest that the PDGFRβ-CD44 is a regulatory axis modulating medulloblastoma progression via c-Myc and targeting PDGFRβ/c-Myc/CD44 may provide a novel therapeutic strategy for the treatment of metastatic medulloblastoma.