Histone variants confer chromatin unique properties and also participate in the regulation of genetic expression through specific deposition and removal machineries. macroH2A1 is one of histone variants and has been found implicating in female X chromosome inactivation and transcriptional repression. However, recent marcoH2A1 has been reported to suppress tumor proliferation through regulating cellular senescence and metabolism under specific situations. The paper reviews the roles of macroH2A1 in tumorigenesis and the molecular mechanisms in regulating genetic expression based on current research progress.