A wide range of cellular activities depends upon endocytic recycling. ARF6, a small molecular weight GTPase, regulates the processes of endocytosis and endocytic recycling in concert with various effector molecules and other small GTPases. This review highlights three critical processes that involve ARF6-mediated endosomal membrane trafficking—cell motility, cytokinesis, and cholesterol homeostasis. In each case, the function of ARF6-mediated trafficking varies—including localization of specific protein and lipid cargo, regulation of bulk membrane movement, and modulation of intracellular signaling. As described in this review, mis-regulation of endocytic traffic can result in human disease when it compromises the cell's ability to regulate cell movement and invasion, cell division, and lipid homeostasis.