FOXR2 encodes a Forkhead-Box transcription factor that has been recently described as a proto-oncogene. In this issue of Cancer Research, Tsai and colleagues present the first pan-cancer study summarizing the prevalence of FOXR2 overexpression beyond rare childhood-onset malignancies. Identification of a previously unknown mechanism of epigenetic activation and the expansion of FOXR2 transcriptional targets enhance the mechanistic understanding of FOXR2-driven malignancy, with the potential to uncover new therapeutic opportunities.See related article by Tsai et al., p. 2980