Colorectal cancers (CRCs) are characterized by global hypomethylation and promoter-specific DNA methylation. A subset of CRCs with extensive and co-ordinate patterns of promoter methylation has also been identified, termed the CpG-island methylator phenotype. Some genes methylated in CRC are established tumor suppressors; however, for the majority, direct roles in disease initiation or progression have not been established. Herein, we examine functional evidence of specific methylated genes contributing to CRC pathogenesis, focusing on components of commonly deregulated signaling pathways. We also review current knowledge of the mechanisms underpinning promoter methylation in CRC, including genetic events, altered transcription factor binding, and DNA damage. Finally, we summarize clinical trials of DNA methyltransferase inhibitors in CRC, and propose strategies for enhancing their efficacy.