Cell migration is a fundamental aspect of a multitude of physiological and pathological processes, including embryonic development, inflammation, angiogenesis, and cancer progression. A variety of proteins are essential for cell migration, but context-specific signaling pathways and promigratory proteins must now be identified for our understanding of cancer biology to continue to advance. In this review, we focus on the emerging roles of Girdin (also designated KIAA1212, APE, GIV, and HkRP1), a novel component of the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway that is a core-signaling transduction pathway in cancer progression. Girdin is expressed in some types of cancer cells and immature endothelial cells, and is therefore at the crossroads of multiple intracellular processes, including reorganization of the actin cytoskeleton, endocytosis, and modulation of Akt activity, which ultimately lead to cancer invasion and angiogenesis. It also acts as a nonreceptor guanine nucleotide exchange factor (GEF) for Galphai proteins. A significant observation is that Girdin, although vital for cancer progression and postnatal vascular remodelling, is dispensable for cell migratory events during embryonic development. These findings suggest that Girdin and its interacting proteins are potential pharmaceutical targets for cancer therapies and pathological anigiogenesis, including tumor angiogenesis.