Intracellular membrane trafficking requires the complex interplay of several classes of trafficking proteins. Rab proteins, the largest subfamily of the Ras superfamily of small G-proteins, are central regulators of all aspects of intracellular trafficking processes including vesicle budding and uncoating, motility, tethering and fusion. In the present paper, we discuss the discovery, evolution and characterization of the Rab GTPase family. We examine their basic functional roles, their important structural features and the regulatory proteins which mediate Rab function. We speculate on outstanding issues in the field, such as the mechanisms of Rab membrane association and the co-ordinated interplay between distinct Rab proteins. Finally, we summarize the data implicating Rab proteins in an ever increasing number of diseases.