CD28‐delivered costimulatory signals are required to induce NF‐κB activation in response to TCR stimulation. We have recently demonstrated that the mitogen‐activated kinase kinase 1 (MEKK1), a kinase known to regulate the c‐jun N‐terminal kinase (JNK) pathway, is also involved in the CD28‐ and TCR‐induced inhibitor of κB factor (IκB) kinases (IKK) and NF‐κB activation. Searching for molecules that couple TCR and CD28 to MEKK1, we found that the guanine nucleotide exchange factor Vav synergized with CD28 stimulation in Jurkat cells to induce NF‐κB transcriptional activity through the activation of IKKα and IKKβ. Dominant negative mutants of Vav inhibited TCR‐ and CD28‐NF‐κB‐dependent transcription by interfering with the activation of the IKK complex. Blocking Rac signaling downstream of Vav by dominant negative RacN17 exerts similar effects on IKK and NF‐κB activation after TCR/CD28 stimulation. Finally, Vav‐induced NF‐κB activation in CD28 costimulated cells was inhibited by dominant negative MEKK(KM). These results identify Vav, Rac‐1 and MEKK1 as components of a common pathway regulating both NF‐κB and AP‐1 that contributes to full activation of the CD28 response element (CD28RE).