The structural GDP/GTP cycle of Arf proteins is implemented by switch regions that change their conformations in response to the nature of their interactions. They include the classical switch regions in the nucleotide-binding site, and a unique switch region located on the opposite side of the protein. These switch regions communicate with each other and couple activation of Arfs by GTP to their recruitment to membranes. Variations in this cycle determine the specificity and differences in Arf1 and Arf6 signaling. The role of guanine nucleotide exchange factors (GEFs) as key players in the implementation of the nucleotide/membrane coupling is also described. A particular emphasis is given to the inhibition of GEF-activated nucleotide exchange by the drug Brefeldin A and by a GEF point mutation, as tools to trap intermediate states of the reaction. Taken together, structural and biochemical studies yield a comprehensive model for one of the most remarkable nucleotide cycle found in G proteins.