STATs (signal transducer and activator of transcription) play important roles in numerous cellular processes including immune responses, cell growth and differentiation, cell survival and apoptosis, and oncogenesis. In contrast to many other cellular signaling cascades, the STAT pathway is direct: STATs bind to receptors at the cell surface and translocate into the nucleus where they function as transcription factors to trigger gene activation. However, STATs do not act alone. A number of proteins are found to be associated with STATs. These STAT-interacting proteins function to modulate STAT signaling at various steps and mediate the crosstalk of STATs with other cellular signaling pathways. This article reviews the roles of STAT-interacting proteins in the regulation of STAT signaling.