STAR (Signal Transduction and Activation of RNA) proteins owed their name to the presence in their structure ofa RNA-binding domain and several hallmarks of their involvement in signal transduction pathways. In many members of the family, the STAR RNA-binding domain (also named GSG, an acronym for GRP33/Sam68/ GLD-1) is flanked by regulatory regions containing proline-rich sequences, which serve as docking sites for proteins containing SH3 and WW domains and also a tyrosine-rich region at the C-terminus, which can mediateprotein-protein interactions with partners through SH2 domains. These regulatory regions contain consensus sequences for additional modifications, including serine/threonine phosphorylation, methylation, acetylation and sumoylation. Since their initial description, evidence has been gathered in different cell types and model organisms that STAR proteins can indeed integrate signals from external and internal cues with changes in transcription and processing of target RNAs. The most striking example of the high versatility of STAR proteins is provided by Sam68 (KHDRBS1), whose function, subcellular localization and affinity for RNA are strongly modulated by several signaling pathways through specific modifications. Moreover, the recent development of genetic knockout models has unveiled the physiological function of some STAR proteins, pointing to a crucial role of their post-translational modifications in the biological processes regulated by these RNA-binding proteins. This chapter offers an overview of the most updated literature on the regulation of STAR proteins by post-translational modifications and illustrates examples of how signal transduction pathways can modulate their activity and affect biological processes.