The interactions and functions of protein inhibitors of activated STAT (PIAS) proteins are not restricted to the signal transducers and activators of transcription (STATs), but PIAS1, -2, -3 and -4 interact with and regulate a variety of distinct proteins, especially transcription factors. Although the majority of PIAS-interacting proteins are prone to modification by small ubiquitin-related modifier (SUMO) proteins and the PIAS proteins have the capacity to promote the modification as RING-type SUMO ligases, they do not function solely as SUMO E3 ligases. Instead, their effects are often independent of their Siz/PIAS (SP)-RING finger, but dependent on their capability to noncovalently interact with SUMOs or DNA through their SUMO-interacting motif and scaffold attachment factor-A/B, acinus and PIAS domain, respectively. Here, we present an overview of the cellular regulation by PIAS proteins and propose that many of their functions are due to their capability to mediate and facilitate SUMO-linked protein assemblies.