Cancer metastasis is a complex, dynamic process that begins with dissemination of cells from the primary tumor and culminates in the formation of clinically detectable, overt metastases at one or more discontinuous secondary sites. Evidence from in vivo video microscopy as well as PCR and immunohistochemical studies suggest that cancer cell dissemination is an early event in tumor progression and that cells may persist in a potentially dormant state for a prolonged period. Similarly, the mechanisms by which these disseminated cells initiate growth and complete the process of metastatic colonization remain largely unknown. Understanding signal transduction pathways regulating this final step of metastasis is therefore critical for successful clinical management. While genetic mutations or epigenetic changes may be required for a cell or group of cells to separate and survive distant from the primary tumor, the microenvironment within secondary tissues plays a substantial role in influencing whether disseminated cells survive and proliferate. Our work is focused on using metastasis suppressor proteins to gain insight into why the majority of disseminated cells, which should be fully malignant, do not proliferate immediately at secondary sites. The translational goal of this work is to identify targets for inhibiting metastatic growth and prolonging disease-free survival.