The IkB kinase complex (IKK) is central to the activation of NF-kB, a critical transcription factor governing expression of genes involved in cell proliferation and anti-apoptotic responses. Mice with genetic disruptions of the Ikkb or Ikkg gene loci die during embryogenesis due to severe hepatic apoptosis. We now show that Ikkb gene deficiency promotes migration and proliferation of mouse embryo fibroblast cells. Morphological analyses revealed an unusual protrusion of the cytoplasm in Ikkb-/- cells when cultured at a lower density. In a Boyden chamber assay, Ikkb-/- cells exhibited a high rate of invasion and migration. Enhanced formation of actin stress fibers was also observed in the Ikkb-/- cells. Mechanistic studies indicated that IKKb affects expression of proteins involved in the assembly of cytoskeleton and cell movement. Furthermore, re-expression of Ikkb and antioxidant treatment in Ikkb-/- cells caused a reversal of protrusive phenotype and high motility, respectively. Furthermore, elimination of reactive oxygen species (ROS) blocked expression of snail and subsequently, de-repressed E-cadherin expression. Although the underlying mechanism is likely entangled and complicated, the data presented indicate that generation of ROS played key role in the morphological and mobility changes in Ikkb-/- cells. These data, thus, suggest that IKKb provides inhibitory signals for cell mobility and growth. Deficiency in the Ikkb gene promotes cell mobilization, at least partially, through a ROS-dependent mechanism.