Because colorectal cancer (CRC) is a leading cause of cancer mortality in the Western industrialized world, future chemopreventive strategies will be of high socioeconomic importance. Lower CRC incidences in Far Eastern countries in part may be attributed to high nutritional intake of soy and its abundance in phytoestrogens. Phytoestrogens are plant-derived substances which, due to molecular similarities to endogenous estrogens, distinctly interact with estrogen receptors ERalpha and ERbeta. Both genomic and nongenomic mechanisms have been shown to be responsible for possible anticarcinogenic properties of phytoestrogens, such as induction of apoptosis and inhibition of tyrosine kinases and DNA topoisomerases. This chapter provides a comprehensive review of a variety of studies exploring possible relations between phytoestrogen uptake and CRC risk. While in vitro and animal studies in general are somewhat supportive of a protective role of phytoestrogens against CRC, epidemiological work so far performed does not allow any conclusion on this issue. Studies about mechanisms of phytoestrogenic action against CRC development have been evaluated as well. Because estrogens, vitamin D, and calcium are frequently suggested to be important in CRC prevention, studies concentrating on interactions of phytoestrogens with these substances have been performed. Although support in evidence for a protective effect of phytoestrogens against CRC has increased over the last decade, it is still too early to give a definite recommendation, especially in view of enduring inconsistencies about concentrations most likely to be effective. Further experimental, and particularly epidemiological, studies are required to advance our understanding of the role of phytoestrogens against colon carcinogenesis.