Vascular smooth muscle cells (VSMCs) are normally quiescent and non-migratory, regulating the contraction and relaxation of blood vessels to control the vascular tone. In response to arterial injury, these cells become active; they proliferate, secrete matrix proteins, and migrate, and thereby contribute importantly to the progression of several cardiovascular diseases. VSMC migration specifically supports atherosclerosis, restenosis after catheter-based intervention, transplant vasculopathy, and vascular remodeling during the formation of aneurysms. The atypical cadherin FAT1 is expressed robustly in activated VSMCs and promotes their migration. A positive role of FAT1 in the migration of other cell types, including neurons, fibroblasts, podocytes, and astrocyte progenitors, has also been described. In cancer biology, however, the effect of FAT1 on migration depends on the cancer type or context, as FAT1 either suppresses or enhances cancer cell migration and invasion. With this review, we describe what is known about FAT1’s effects on cell migration as well as the factors that influence FAT1-dependent migration. In VSMCs, these factors include angiotensin II, which activates FAT1 expression and cell migration, and proteins of the Atrophin family: Atrophin-1 and the short isoform of Atrophin-2, which promote VSMC migration, and the long isoform of Atrophin-2, which exerts negative effects on FAT1-dependent VSMC migration.