Chemoprevention is the long-term use of different chemical agents, both synthetic and natural, to prevent or delay the onset of disease. Since colorectal cancer has a significant environmental component, it is an ideal disease in which to evaluate the potential benefits of chemopreventive agents. The polyamines, spermine, spermidine and putrescine have been involved in almost all the steps of colorectal tumorigenesis. Consequently, polyamine biosynthesis and catabolism can be considered as promising targets for cancer chemoprevention. A variety of drug formulations have been tested for their efficacy in affecting polyamines in a strategy of colorectal cancer prevention. Different molecules, such as biosynthesis inhibitors and catabolism inducers, have been proposed alone or in combination with other drugs proved to diminish the colorectal cancer risk. Interestingly, also diet can play a role in cancer prevention by affecting polyamines. Several dietary components, such as probiotics or flavonoids, have been shown to affect the polyamine metabolic pathway in colorectal neoplastic tissue. On the other hand, the polyamines ingested with diet might contrast the above cited effects shown by both drugs and nutritional factors. It is, therefore, fundamental to acquire more data also on these aspects in view of an innovative approach to colorectal oncology. This review summarizes data on the role of polyamine metabolism in neoplastic transformation of colorectal mucosa and as possible target for colorectal cancer chemoprevention. Attention will be focused on the influence of drugs and nutritional factors on polyamine metabolism, as well as the role played by dietary polyamines.