ARF-GEFs are a family of guanine-nucleotide exchange factors catalyzing the exchange of GDP for GTP on ADP-ribosylation factor. Large ARF-GEFs are highly conserved in all eukaryotes. It is an important regulator in both membrane dynamics and protein trafficking. Significant progress has been made in elucidating the structure, subcellular localization, and physiological functions of ARF-GEFs as a hot topic of cell biology recently. In this review, the character-istics and distribution of ARF-GEFs in different species, and recent research progress of ARF-GEFs and their regulation system are summarized.