Dock180 superfamily of proteins has been recently identified as novel, unconventional guanine nucleotide exchange factors (GEF) for Rho-family GTPases. Unlike most other GEFs for Rho-family GTPases, Dock180 family members do not contain the characteristic Dbl homology (DH) domain. Instead, they use a conserved "Docker" or "CZH2" domain to mediate the nucleotide exchange on Rho-family GTPases. The Dock180 family members are evolutionarily conserved from worms to mammals. They play critical roles in a number of biological processes essential for the normal development of entire organisms, as well as for the physiological responses of these organisms, including removal of apoptotic cells and directed cell migration in C. elegans; myoblast fusion, and dorsal closure in Drosophila; lymphocyte migration, T-cell activation, tumor metastasis, HIV infection, and development of neuronal degenerative diseases in mammals. All these biological activities of the Dock180 family members have been linked to their ability to activate their specific GTPase substrate. At least four members of the Dock180 family bind to another evolutionarily conserved protein ELMO to optimally activate the Rac GTPase. The best characterized is the Rac activation by the Dock180-ELMO complex. ELMO modulates the Rac activation by Dock180 by means of at least three distinct mechanisms: helping Dock180 stabilize Rac in its nucleotide-free transition state; relieving a self-inhibition of Dock180; and targeting Dock180 to the plasma membrane to gain access to Rac. Thus, Dock180 and ELMO function together as a bipartite GEF to optimally activate Rac on upstream stimulation to mediate the engulfment of apoptotic cells and cell migration.