Cytokines activate multiple signal transduction pathways to regulate gene expression. STATs and NF-kB are two important families of transcription factors activated by cytokines. Abnormal regulation of STAT and NF-kB activities has been associated with human diseases. The protein inhibitor of activated STAT (PIAS) protein family has been proposed to interact with over 60 proteins, many of which are transcription factors involved in the immune system. PIAS proteins regulate transcription through several mechanisms, including blocking the DNA-binding activity of transcription factors, recruiting transcriptional co-repressors and promoting protein sumoylation. This article is to review the role of PIAS proteins in the regulation of STAT and NF-kB signaling pathways.