A subset of Rab GTPases have instrumental roles in the biogenesis, trafficking, docking and exocytosis of secretory granules, secretory lysosomes and synaptic vesicles. The four Rab3 isoforms and the two Rab27 isoforms are the main members of this family of “secretory Rabs.” Redundancy between the isoforms and between the Rab3 and Rab27 proteins has made the functional characterization of these proteins difficult. Data collected from different cell types suggest that the main role of Rab27 is to promote the recruitment of secretory vesicles at the release sites, while that of Rab3 is to control the number of ready-to-fuse vesicles. However, many observations that cannot be incorporated into this simplified scheme suggest that Rab3 and Rab27 have overlapping functions at different stages of the “life cycle” of secretory vesicles. Consistent with this, while some effector molecules are specific for Rab3 or Rab27, several interact with both of them.