Background: GBF1, BIG1, and BIG2 are guanine nucleotide exchange factors (GEFs) that activate ARFs to regulate secretory traffic. Results: GBF1 activity promotes subsequent recruitment of BIG1/2. Conclusion: The three GEFs are functionally coupled in a GEF/ARF/GEF cascade. Significance: Coupling integrates all coating events within the pathway to simultaneously regulate passage of cargo through multiple compartments. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.