Recent human and mouse genetic studies have highlighted important contributions of several small GTPases, in particular Rab8a, Cdc42, and Rab11a, to the proper morphogenesis and function of the mature intestinal epithelia. Additional insights about the involvement of these factors in maintaining intestinal stem cell homeostasis have also been obtained. These studies suggest a conserved vesicular and membrane trafficking program utilized by the gastrointestinal tissue to support the rapid epithelial cell turnover and the highly sophisticated physiology of mature epithelial cells.