Sp1 is a ubiquitously expressed, prototypic C2H2-type zinc finger-containing DNA binding protein that can activate or repress transcription in response to physiologic and pathological stimuli. It was originally found to selectively transactivate the early and late simian virus 40 promoters without inffuencing numerous other promoters (16) and has since been shown to regulate the expression of thousands of genes implicated in the control of a diverse array of cellular processes, such as cell growth (26, 57), differentiation (48), apoptosis (26), angiogenesis (43), and immune response (25), to name just a few. Sp1 is a 785-amino-acid, 100-to 110-kDa nuclear transcription factor which regulates gene expression via multiple mechanisms. It binds GC-rich motifs (such as 5!-G/T-GGGCGG-G/AG/AC/T-3! or 5!-G/TG/A-GGCG-G/TG/AG/AC/T-3!) with high affinity (4, 27, 28) and can regulate the expression of TATA-containing and TATA-less genes via protein-protein interactions or interplay with other transcription factors (47), such as Ets-1 (56), c-myc (51), c-Jun (44), Stat1 (6), and Egr-1 (31), and/or components of the basal transcriptional machinery. Sp1 has been linked to chromatin remodeling through interactions with chromatin-modifying factors such as p300 (62) and histone deacetylases (HDACs)(71). Sp1 was once thought to serve mainly as a constitutive activator of housekeeping genes. However, growing evidence indicates that phosphorylation, acetylation, sumoylation, ubiquitylation, and glycosylation are among the posttranslational modifications that can inffuence the transcriptional activity and stability of Sp1. Here we will discuss recent developments in our understanding of the role of posttranslational modifications inffuencing Sp1-dependent transcription, focusing mainly on phosphorylation.