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The small GTPases of the ADP-ribosylation factor (Arf) family are key initiators of various physiological processes including secretion, endocytosis, phagocytosis and signal transduction. Arf family proteins function to mediate recruitment of cytosolic effectors to specific subcellular compartments. This process facilitates Arf effectors to perform cargo recognition, lipid modification or other cellular functions. Blocking the activities of Arf family proteins inhibits secretion of important molecules from the cell and also inhibits cellular uptake of nutrients. Defects in Arfs or their regulatory proteins are related to various inherited diseases, including X-linked intellectual disability (XLID), Joubert syndrome, Bardet-Biedl syndrome and cilia dysfunction. Thus, studying molecular mechanisms of Arf-regulated intracellular activities represents an opportunity to understand these diseases etiology and develop novel therapeutic strategies.