The small GTPase RhoB is distinguished from other Rho proteins by its unique subcellular localization in endosomes, multivesicular bodies, and nucleus. Despite high sequence homology with RhoA and RhoC, RhoB is mainly associated with tumor suppressive function, while RhoA and RhoC support oncogenic transformation in most malignancies. RhoB regulates the endocytic trafficking of signaling molecules and cytoskeleton remodeling, thereby controlling growth, apoptosis, stress response, immune function, and cell motility in various contexts. Some of these functions may be ascribed to RhoB’s unique subcellular localization to endocytic compartments. Here we describe the pleiotropic roles of RhoB in cancer suppression in the context of its subcellular localization, and we discuss possible therapeutic avenues to pursue and highlight priorities for future research.