Natural polyamines (PA) are cationic molecules affecting cell growth and proliferation. An association between increased polyamine biosynthesis and inflammation-induced carcinogenesis has been recognised. On the other hand, there are indications that inflammatory stimuli can up-regulate polyamine catabolism and that altered polyamine metabolism could affect pro- and anti-inflammatory cytokines. Since the polyamine content is strictly related to cell growth, a consistent number of evidences relate polyamine metabolism dysfunction with cancer. The increase of polyamine levels in malignant and proliferating cells attracted the interest of scientists during last decades, addressing polyamine depletion as a new strategy to inhibit carcinogenesis. Several studies suggest that PA also play an important role in neurodegeneration, but the mechanisms by which they participate in neuronal death are still unclear. Furthermore, the role of endogenous PA in normal brain functioning is yet to be elucidated. The consequences of an alteration of polyamine metabolism have also been approached in vivo with the use of transgenic animals overexpressing or devoid of some enzymes involved in polyamine metabolism. In the present work we review the experimental investigation carried out on inflammation, cancerogenesis and neurodegeneration using transgenic animals engineered as models for polyamine research.