This chapter provides an overview of how the polyamine pathway has been exploited as a target for the treatment and prevention of multiple forms of cancer, since this pathway is disrupted in all cancers. It is divided into three main sections. The first explores how the polyamine pathway has been targeted for chemotherapy, starting from the first drug to target it, difluoromethylornithine (DFMO) to the large variety of polyamine analogues that have been synthesised and tested throughout the years with all their potentials and pitfalls. The second section focuses on the use of polyamines as vectors for drug delivery. Knowing that the polyamine transport system is upregulated in cancers and that polyamines naturally bind to DNA, a range of polyamine analogues and polyamine-like structures have been synthesised to target epigenetic regulators, with encouraging results. Furthermore, the use of polyamines as transport vectors to introduce toxic/bioactive/fluorescent agents more selectively to the intended target in cancer cells is discussed. The last section concentrates on chemoprevention, where the different strategies that have been undertaken to interfere with polyamine metabolism and function for antiproliferative intervention are outlined and discussed.