In this review, we review updates in the knowledge of the diverse roles of KDM5 in cancer, highlight the recent understanding regarding the molecular mechanisms through which KDM5 is engaged in transcriptional output, including our findings that KDM5A supports MYC-driven transcription by maintaining the H3K4 methylation cycle through H3K4me3 demethylation, and further discuss the possibility of the application of KDM5 inhibitors in cancer therapy. This evidence concerns the gene MYC and cancer.