Regulators of G-protein signaling (RGS) proteins are negative regulators of heterotrimeric guanine-nucleotide-binding proteins (G-proteins) by activating intrinsic GTPase activity of G alpha and thereby terminating G-protein coupled receptor-associated signal transduction. RGS8 belongs to B/R4 subfamily of RGS proteins and is expressed in the central nervous system, especially dense in cerebellar Purkinje cells. RGS8 binds specifically to G alpha o and G alpha i3 in vitro and activates their intrinsic GTPase activities. To investigate the role of RGS8 in vivo, we generated mice lacking RGS8 by gene targeting in embryonic stem (ES) cells using Cre/loxP system. RGS8 null mutant mice were viable, fertile and showed apparently normal development. Histological analysis showed no apparent abnormalities in morphology of cerebellar layer or Purkinje cells in RGS8 null mutant mice.