The small GTPase Rab5 has been frequently studied in the context of intracellular trafficking, but evidence obtained more recently has implicated Rab5 as a critical regulator of cell adhesion, migration and invasion in both normal and tumor cells. These recent findings showing that Rab5 promotes Rac1 activation and focal adhesion dynamics have highlighted the question as to what the upstream regulators of Rab5 activity might be and how these are connected to cell migration. The efforts to shed light on this issue identified in metastatic cancer cells a novel Caveolin-1/p85α/Rab5/Tiam1/Rac1 signaling axis relevant to cancer cell migration and invasion. In this addendum, we highlight aspects concerning Rab5 regulation in this context.