Dock180-related proteins are genetically conserved from Drosophila and C. elegans to mammals and are atypical types of guanine-nucleotide exchange factors (GEFs) for Rac and/or Cdc42 of small GTPases of the Rho family. Eleven members of the family occur in mammalian cells, each playing key roles in many aspects of essential cellular functions such as regulation of cytoskeletal organization, phagocytosis, cell migration, polarity formation, and differentiation. This review will summarize the newly accumulated findings concerning the Dock180-related proteins' molecular and cellular functions, emphasizing the roles of these proteins in neuronal cells and glial cells as well as their interactions in the central and peripheral nervous systems.