Specific protein 1 (Sp1), the first transcription factor to be isolated, regulates the expression of numerous genes involved in cell proliferation, apoptosis, and differentiation. Recent studies found that an increase in Sp1 transcriptional activity is associated with the tumorigenesis. Moreover, post-translational modifications of Sp1, including glycosylation, phosphorylation, acetylation, sumoylation, ubiquitination, and methylation, regulate Sp1 transcriptional activity and modulate target gene expression by affecting its DNA binding activity, transactivation activity, or protein level. In addition, recent studies have investigated several compounds with anti-cancer activity that could inhibit Sp1 transcriptional activity. In this review, we describe the effect of various post-translational modifications on Sp1 transcriptional activity and discuss compounds that inhibit the activity of Sp1.