Members of the MAGUK family proteins cluster receptors and intracellular signaling molecules at the neuronal synapse. We report that genetic inactivation of the MAGUK family protein CARD11/Carma1/Bimp3 results in a complete block in T and B cell immunity. CARD11 is essential for antigen receptor- and PKC-mediated proliferation and cytokine production in T and B cells due to a selective defect in JNK and NFkappaB activation. Moreover, B cell proliferation and JNK activation were impaired upon stimulation of TLR4 with lipopolysaccharide, indicating that CARD11 is involved in both the innate and adaptive immune systems. Our results show that the same family of molecules are critical regulators of neuronal synapses and immune receptor signaling.