Mammary tumors are among the most common cancers in female dogs and cats. And although surgical removal remains the most widely accepted treatment option, the high incidence of tumor recurrence and metastatic disease after surgical resection shows that current treatment regimens are unsatisfactory and that there is an urgent need for better treatment options. In general, cancer is induced by the accumulation of altered gene regulation that can be caused by abnormalities in the DNA sequence (genetic mutations) or by changes in gene expression profiles (epigenetic dysregulation). Because of the reversible nature of the latter, the potential of epigenetic modifiers in human breast cancer drug development has gained significant interest. In contrast, the potential of such epigenetic drugs to treat mammary cancer in small companion animals remains largely unexplored. We are currently investigating the efficacy of the DNA methyltransferase (DNMT) inhibitor 5-Azacytidine (5-AzaC) and the protein arginine deiminase (PAD) inhibitor Cl-amidine to reduce canine and feline tumor growth in vitro and in vivo. We recently found promising anti-cancer effects in vitro and are now following up with in vivo studies, which will ultimately provide the basis for future clinical trials in dogs and cats with mammary cancer.