Cytoskeleton rearrangement is necessary for tumor invasion and metastasis. Cellular molecules whose role is to regulate components of the cytoskeletal structure can dictate changes in cellular morphology. One of these molecules is the suppressor of tumor metastasis Nm23-H1. The level of Nm23-H1 expression has been linked to the invasiveness and metastatic potential of human cancers including melanoma and breast cancer. In this report, we demonstrate an interaction between the suppressor of tumor metastasis Nm23-H1, and Dbl-1, an oncoprotein which is associated with guanine exchange and belongs to a family of Guanine Exchange Factors (GEF). Nm23-H1 also was shown to bind pDbl which is the proto-oncoprotein of Dbl. Interestingly, the interaction between Nm23-H1 and Dbl-1 rescues the suppression of the cell motility activity Nm23-H1. Moreover, this interaction results in loss of the ability of the Dbl-1 oncoprotein to function as a GEF for the critical Rho-GTPase family member Cdc42. The loss of GTP loading onto Cdc42 resulted in a dramatic reduction in adhesion stimulated ruffles and suggests that Nm23-H1 can negatively regulate cell migration and tumor metastasis by modulating the activity of Cdc42 through direct interaction with Dbl-1.