MicroRNAs, detected in mitochondria, have been termed mitomiRs. Among them, mitomiR-2392 was shown to be enriched in tongue squamous cell carcinoma cells and to regulate their chemoresistance by reprogramming cell metabolism. Mechanistically, mitomiR-2392 recognizes and binds target sequences in the H-strand of mtDNA with AGO2 and partially inhibits mtDNA transcription. MitomiR-2392 may be a useful biomarker for clinical risk evaluation and an attractive target to overcome chemoresistance. For details, see article by Fan and colleagues on page 1069.