MDM2 binding protein (MTBP) is a protein that interacts with oncoprotein murine double minute (MDM2), a major inhibitor of the tumor suppressor p53. Overexpression of MTBP leads to p53-independent cell proliferation arrest, which is in turn blocked by simultaneous overexpression of MDM2. Importantly, reduced expression of MTBP in mice increases tumor metastasis and enhances migratory potential of mouse embryonic fibroblasts regardless of the presence of p53. Clinically, loss of MTBP expression in head and neck squamous cell carcinoma is associated with reduced patient survival, and is shown to serve as an independent prognostic factor when p53 is mutated in tumors. These results indicate the involvement of MTBP in suppressing tumor progression. Our recent findings demonstrate that overexpression of MTBP in human osteosarcoma cells lacking wild-type p53 inhibits metastasis, but not primary tumor growth, when cells are transplanted in femurs of immunocompromised mice. These data indicate that MTBP functions as a metastasis suppressor independent of p53 status. Furthermore, overexpression of MTBP suppresses cell migration and filopodia formation, in part, by inhibiting function of an actin crosslinking protein α-actinin-4. Thus, increasing evidence indicates the significance of MTBP in tumor progression. We summarize published results related to MTBP function and discuss caveats and future directions in this review article.