Early steps of endocytosis involve budding and formation of endocytic vesicles from the plasma membrane, movement of the vesicles along cytoskeleton, and fusion with early endosomes. The Rab5 subfamily of GTPases (Rab5, Rab21, and Rab22) are localized to early endosomes and plasma membrane and play an important role in regulation of early endocytosis and signal transduction, via interactions with multiple effector proteins. Rab5, Rab21, and Rab22 share some common effectors, but differentially interact with other effectors and regulators, and exhibit distinct functions in early endocytosis. The interplay of the early endocytic Rabs is illustrated by the Rab22-Rab5 cascade in which Rab22-GTP recruits Rabex-5 (a Rab5 GEF) to early endosomes for activation of Rab5 and stimulation of early endosome fusion. This and other functions of Rab5, Rab21, and Rab22 in the formation and uncoating of endocytic vesicles, the vesicle movement on cytoskeleton, and the early endosome fusion are discussed in this review.