The role of post-translational modification of cell proteins with polyamines, a reaction catalyzed by a tissue tranglutaminase (TG, EC 2.3.2.13), in the induction of cell differentiation, represents an intriguing strategy to control cell proliferation and metastatic ability of different tumor cell lines. In this review, we focus our attention on the metabolic aspects of some natural compounds (methylxantines, retinoids and flavonoids) responsible of their antitumor effects exerted through the induction of TG activity in cancer cells.