MYBL2 (B-MYB), a member of the MYB family of transcription factor genes, regulates the expression of genes in the process of tumorigenesis. Many studies have shown that MYBL2 is highly expressed in several human malignancies including pancreatic ductal adenocarcinoma (PDAC). Overexpression of MYBL2 might serve as a novel prognostic biomarker in PDAC patients. MYBL2 is a key downstream factor of Akt/FoxM1 signaling to promote the progression of human glioma and could be a new candidate gene for molecular targeting therapy and biomarker for radiotherapy of glioma. MYBL2 (alias B-Myb) is a physiological regulator of cell cycle progression, cell survival, and cell differentiation. When deregulated in cancer cells, MYBL2 mediates the deregulation of these properties. MYBL2 and players of its downstream transcriptional network can be used as prognostic and/or predictive biomarkers as well as potential therapeutic targets to offer less toxic and more specific anti-cancer therapies in the future.