FOXK2 is a transcription factor known to regulate a wide range of biological processes that are critically involved in determining cell fate. Increasing evidence shows aberrant FOXK2 expression in some tumors, with crucial biological and clinical impacts. It is important to note that the molecular mechanisms contributing to FOXK2 gene deregulation are poorly understood for most cancers. In this review, we systematically describe the FOXK2 gene expression profile across distinct tumor types and discuss its potential utility as a prognostic and diagnostic molecular marker. Notably, we explore emerging mechanisms accounting for FOXK2 deregulation, focusing on genetic and transcriptional modifications, such as gene methylation, mutation and copy number variations.