The p90 ribosomal S6 kinases (RSKs) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. In humans, the RSK family consists of four isoforms (RSK1 to -4). RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional. Theses kinase dimains are activated in a sequential manner by a series of phosphorylations. RSK regulates gene expression via association and phosphorylation of transcriptional regulators including c-Fos, estrogen receptor, NFκB/IκB α, cAMP-response element-binding protein (CREB). ERK activates the C-terminal kinase of RSK, leading to activation of the N-terminal kinase. Members of the RSK family are present in the cytoplasm as well as the nucleus. Addition of growth factor to the cells results in the activation of both cytosolic and nuclear RSK and the translocation of the cytosolic RSK into the nucleus upon activation. The activation and nuclear translocation of RSK result in phosphorylation and activation of transcription factors. Serine/threonine kinase that may play a role in mediating the growth-factor and stress induced activation of the transcription factor CREB.