SPINOPHILIN (SPN, PPP1R9B or NEURABIN-2) is a multifunctional protein that regulates protein-protein interactions in different cell signaling pathways. SPN is also one of the regulatory subunits of protein phosphatase 1 (PP1), implicated in the dephosphorylation of retinoblastoma protein (pRB) during cell cycle. The SPN gene has been described as a tumor suppressor in different human tumor contexts, in which low levels of SPN are correlated with a higher grade and worse prognosis. In addition, mutations of the SPN protein have been reported in human tumors. Recently, an oncogenic mutation of SPN, A566V, was described, which affects both the SPN-PP1 interaction and the phosphatase activity of the holoenzyme, and promotes p53-dependent tumorigenesis by increasing the cancer stem cell (CSC) pool in breast tumors. Thus, the loss or mutation of SPN could be late events that promotes tumor progression by increasing the CSC pool and, eventually, the malignant behavior of the tumor.