The family of ribosomal S6 kinases (Rsks), designated Rsk-1, Rsk-2 and Rsk-3, are important signaling intermediates that mediate responses to a broad range of ligand-activated receptor tyrosine kinases. It has been established that Rsk-3 is not activated by MAP kinase in vitro, unlike Rsk-1 and Rsk-2. A unique feature common to the three members of the Rsk family is that each possesses two non-identical complete kinase catalytic domains. The Rsk family amino-terminal kinase domain is phosphorylated on Ser 227 by 3-phosphoinositide-dependent protein kinase-1 (PDK1), which increases the kinase activity of Rsk. In the carboxy-terminal kinase domain, Rsk-1 and Rsk-2 are autophosphorylated on Ser 380 and Ser 386, respectively, which mediates the docking of PDK1 to Rsk in order to promote phosphorylation of substrates, such as histone H3.