Introduction The four members of the p90 ribosomal S6 kinase (RSK) family are serine/threonine protein kinases, which are phosphorylated and activated by ERK1/2. RSK1/2/3 are further phosphorylated by PDK1. Receiving inputs from two major signaling pathways places RSK as a key signaling node in numerous pathologies. A plethora of RSK1/2 substrates have been identified, and in the majority of cases the causative roles these RSK substrates play in the pathology are unknown.