Colorectal cancer is one of the leading causes of premature death in people worldwide. Due to the fact that malignant conversion of normal colonic cells requires several steps and often proceeds over considerable time periods, primary prevention of this process should include several approaches, with optimization of nutrition and diet being among most important. During past decades, several groups of chemicals (both naturally occurring as well as synthetic) have been studied in terms of their potential chemopreventive role in colorectal cancer development. Naturally occurring plant polyphenols have recently come into scientific focus because of their presence in various popular natural products (wine grapes, teas, berries, peanuts) and, more importantly, due to their reported antiproliferative and cytostatic abilities in various in vitro and in vivo models. This review seeks to summarize the currently known targets and mechanisms whereby polyphenolic compounds interfere with colonic cancer cells while evaluating their chemopreventive potential in vivo.