The p90 ribosomal S6 kinase family (RSK1–4) is a group of highly conserved Ser/Thr kinases that act as downstream effectors of the Ras/Raf/MEK/ERK signaling pathway. The RSKs phosphorylate a range of substrates involved in transcription, translation, cell cycle regulation, and cell survival. Although the RSKs have a high degree of sequence homology, their functional differences in cancer are of great interest. Current RSK inhibitors target more than one RSK isoform, and this may limit their efficacy as anticancer agents. Here, we review the structure and function of the RSK kinases, their role in cancer growth and survival, and their potential as modulators of chemoresistance. In addition, we summarize the development of current RSK inhibitors and their limitations.