Polyphenolic compounds are widely distributed in the plant kingdom and the anticancer benefits obtained from their consumption have been studied extensively. However, polyphenols are subject to various biotransformation reactions within the human body including methylation. Likewise, naturally occurring polyphenols may contain O-methylations in place of the hydroxyls of the parent compounds. While some studies suggest that methylations can increase the bioavailability of polyphenols, other studies indicate a decrease in the anticancer benefits of methylated polyphenols. This review will focus on the cellular activities of polyphenols, their potential molecular targets and their biological effects after enzymatic methylation. Furthermore, an assessment of the positive and negative aspects of polyphenol methylation on the anticancer activity will be discussed. Finally, the future of polyphenols in both cancer prevention and cancer intervention will be addressed.