Cancer initiation and progression are driven by the concurrent changes in the expression of multiple genes that occur via genetic and epigenetic alterations, leading to either activation of oncogenes and prometastatic genes, or silencing of tumour suppressor genes and to genome rearrangements and instability (Baylin et al., 2001; Widschwendter and Jones, 2002; Szyf, 2005; Stefanska et al., 2011a). Epigenetic modifications have attracted a significant amount of attention in the prevention and treatment of different illnesses, with cancer at the forefront, mainly due to their reversibility. Epigenetics refers to layers of information in addition to genetics and comprises several components such as DNA methylation, covalent histone modifications, particularly histone acetylation and methylation, and non-coding RNA-related mechanisms (Razin and Riggs, 1980; Strahl and Allis, 2000; Jenuwein and Allis, 2001; Bergmann and Lane, 2003). Recent findings have reported additional DNA modifications taking place on the methyl group such as hydroxy-methylcytosine and formyl- and carboxy-methylcytosine (Ito et al., 2010), whose biological role remains to be determined. Although catalyzed by different enzymes and controlled by different protein complexes, all the elements of the epigenome influence each other at the level of the chromatin structure (Razin and Riggs, 1980; Strahl and Allis, 2000; Bergmann and Lane, 2003). DNA hypomethylation, histone acetylation and histone H3K4 methylation have been associated with active chromatin, whereas DNA hypermethylation, histone deacetylation, and histone H3K9 and K27 di- or trimethylation have been found in inactive chromatin regions (Strahl and Allis, 2000). Studies have shown that methylation of DNA results in the recruitment of histone deacetylases (HDACs), which changes chromatin configuration (Nan et al., 1997; Eden et al., 1998). However, alterations in histone marks can also trigger changes in DNA methylation patterns. For example, histone H3K27 methylation and EZH2 histone methyltranferase were required for methylation of EZH2 target genes (Vire et al., 2006), whereas histone acetylation was followed by DNA demethylation (Selker, 1998; Cervoni and Szyf, 2001; Fahrner et al., 2002). Furthermore, changes in chromatin modifications in patients with mutations in the ATRX gene encoding SWI/SNF-like chromatin modifying protein resulted in diverse alterations in DNA methylation patterns (Gibbons et al., 2000). In addition, the third component of the epigenetic machinery, non-coding RNAs were shown to be required for de novo methylation of imprinted loci (Watanabe et al., 2011) and target mRNA of DNA methyltransferases (DNMTs) and HDACs (Rajewsky, 2006; Tuddenham et al., 2006; Zhou et al., 2010). The trilateral relationship between epigenetic modifications (D'Alessio and Szyf, 2006; Iorio et al., 2010) and their dynamic aspect, confirmed by a long list of studies (Weaver et al., 2004; Levenson et al., 2006; Miller and Sweatt, 2007; Feng et al., 2010), can have important implications for human diseases, including cancer where epigenetic factors are known to have a causal and/or contributing role (Baylin et al., 2001; Fahrner et al., 2002; Widschwendter and Jones, 2002; Szyf et al., 2004; Szyf, 2005; Kanwal and Gupta, 2011; Stefanska et al., 2011a). More interestingly, it has been shown that these epigenetic modifications are regulated by a wide range of bioactive food components (Table 1). Compounds from one-carbon metabolism, such as folate, cobalamin, riboflavin, pirydoxine or methionine, are involved in the regulation of the DNA methylation reaction (Scott and Weir, 1998; Slattery et al., 1999; Selhub, 2002). Their deficiency can lead to hepatocellular carcinoma (HCC) (Newberne and Rogers, 1986; Kanduc et al., 1988; Singh et al., 2003; Asada et al., 2006; Ghoshal et al., 2006; Calvisi et al., 2007) and other types of cancer (Kraunz et al., 2006; Bistulfi et al., 2010; Duthie, 2011). Constituents of tea and soybean such as epigallocatechin and genistein, respectively, reverse hypermethylation and the silencing of tumour suppressor genes and inhibit cancer growth (Fang et al., 2005; Lu et al., 2006). Anthocyanins from black raspberries have been shown to suppress DNMT1 and reactivate tumour suppressor genes by demethylating their promoters (Wang et al., 2011). A vegetarian diet has been found to be associated with promoter hypomethylation and the overexpression of a gene encoding the antioxidative enzyme mitochondrial superoxide dismutase, when compared with aged-matched omnivores (Thaler et al., 2009). A lower incidence of sporadic colorectal cancer in the population of southern Italy in comparison with the rest of the Western world has been linked to the presence of Annurca apple in the diet (Fini et al., 2011). Annurca apple contains polyphenols and is especially rich in chlorogenic acid, caffeic acid, catechin, epicatechin, rutin and phloridizin. Treatment of RKO, SW48 and SW480 colorectal cancer cell lines with an extract of Annurca apple polyphenols was shown to reduce DNA methylation in the promoters of hMLH1, p14 and p16 tumour suppressor genes and restore their expression with a concomitant decrease in DNMT1 and DNMT3B protein levels (Fini et al., 2007). Using natural compounds to modulate the epigenome opens an emerging field of nutritional epigenetics and offers a new approach to cancer prevention and treatment. In this review, we summarize recent data suggesting that many bioactive dietary compounds exert anti-cancer effects through epigenetic mechanisms. Furthermore, we highlight the close relationship between all the components of the epigenome and its importance in the evaluation of the effects of a tested agent. We finally discuss the difficulty in assessing the efficacy of natural compounds due to poor bioavailability and their dose-dependent effects.