Cancer metabolism is considered as one of major cancer hallmarks. It is important to understand cancer-specific metabolic changes and its impact on cancer biology to identify therapeutic potentials. Among cancer-specific metabolic changes, a role of serine metabolism has been discovered in various cancer types. Upregulation of serine synthesis pathway (SSP) supports cell proliferation and metastasis. The change of serine metabolism is, in part, mediated by epigenetic modifiers, such as Euchromatic histone-lysine N-methyltransferase 2 and Lysine Demethylase 4C. On the other hand, SSP also influences epigenetic landscape such as methylation status of nucleic acids and histone proteins via affecting S-adenosyl methionine production. In the review, we highlight recent evidences on interactions between SSP and epigenetic regulation in cancer. It may provide an insight on roles and regulation of SSP in cancer metabolism and the potential of serine metabolism for cancer therapy.