Coordinated regulation of vesicle trafficking is critical for the functioning of eukaryotic cells. To maintain cell life in a changing environment, cells must shuttle cargo between intracellular compartments, take in nutrients, and respond to extracellular signals. These tasks are accomplished by activities of the exocytic and endocytic systems and deregulation of either of these systems causes a wide range of human diseases, including cellular transformation, defects in the immune response, and neuronal disorders. I will talk about our recent findings on regulation of vesicle trafficking by small GTPase ADP-ribosylation factors-like 1 (Arl1). Arl1 is an important regulator for Golgi structure and function from yeast to mammal. In yeast, we have shown that Arl1 is activated by the guanine-nucleotide-exchange factors (GEF) Syt1 and inactivated by its GTPase-activating proteins (GAP), Gcs1. Arl1 is activated at several late-Golgi sites via Syt1 and other unidentified GEFs, each in specific molecular complexes that respond to and integrate multiple signals. Activated Arl1 activates the phosphatidylserine flippase Drs2, thereby promoting recruits the golgin protein Imh1 to the Golgi and vesicle transport from the Golgi. We also provide direct evidence of how the flippase Drs2 facilitates Gcs1 targeting to the Golgi and hence its interaction with Arl1. Recently, we demonstrated that while endoplasmic reticulum (ER) stress induced by unfolded proteins influences the distribution of proteins in the Golgi apparatus through signal transduction, it also regulates vesicular transport within the Golgi via activation of Arl1. Our study reveals a sophisticated regulation of Arl1 activity involving its effector and regulatory proteins at the Golgi. Our appreciation of the importance of Arl GTPases in cell biology and biomedicine is continuously increasing as we understand the regulatory mechanisms of these proteins, their regulators and effectors.