As the prototype of a family of transcription factors, Sp1 has been extensively studied and widely reported for its role in gene regulation. The first evidence of Sp1 phosphorylation was reported more than a decade ago. Since then, an increasing number of Sp1 phosphorylation events have been characterized. Recent data demonstrate an important role for the phosphorylation state of Sp1 in the regulation of multiple genes. In this article, we review published literature in four specific areas relating to the phosphorylation of Sp1: (1) signal transduction pathways for Sp1 phosphorylation, (2) mechanisms of Sp1 dephosphorylation, (3) the functional implications of Sp1 phosphorylation, and (4) Sp1 phosphorylation in the lung.