The innate immune system responds to various microbial substances to elicit production of cytokines, chemokines, and costimulatory molecules that regulate activation of the acquired immune system. Although the transcription factor nuclear factor (NF)-kappaB plays central roles in the induction, it remains to be clarified how appropriate genes are selectively activated with appropriate timing and duration by the multifunctional transcription factor after integration of signals activated by invasion of various pathogens. IkappaB-zeta is barely detectable in resting cells and is strongly induced upon stimulation of the innate immune system. The induced IkappaB-zeta associates with the NF-kappaB subunit in the nucleus and regulates its transcriptional activity both positively and negatively depending on genes. Thus, the innate immune system utilizes NF-kappaB as a major transcription factor and modulates its activity in a gene-specific manner by the regulatory factor IkappaB-zeta, which is specifically induced upon stimulation of the innate immune system. This multistep regulation of the transcription would be fundamental in selective expression of genes upon cell activation.