Using the models with intact and targeted deletion or disruption of DNMT1 gene alleles, in this study, we addressed the mechanisms of anti-cancer activity of DNMTi that are mediated (1) primarily by epigenetic mechanism of demethylation and reactivation of expression of tumor suppressor genes; (2) largely through DNA damage effects; and (3) via both modes of action. The gene discussed is DNMT1; the disease is cancer.