Every year more than a million new cancer cases and 600,000 deaths are reported world-wide. Colorectal cancer is the fourth most commonly occurring and second leading cause of cancer deaths in the United States. Significant progress has been made in understanding colorectal cancer through epidemiological, laboratory and clinical studies. Development of metastatic adenocarcinomas is a multistage process occurring over several years during which multiple genetic alterations and pathophysiological changes are associated. Colorectal cancer can be prevented if the transformation of normal colonic crypt cells to malignant can be halted or reversed. Some of the key molecules that are altered significantly and play important roles in colorectal tumor progression are associated with inflammation. Since chronic inflammation is now recognized as a potential risk factor for tumor development, targeting inflammatory pathways has proven effective in preventing formation of colonic tumors and their malignant progression in both preclinical and clinical studies. Synthetic non-steroidal anti-inflammatory drugs (NSAIDS) have been identified as potential colorectal cancer chemopreventive agents; however, most of these synthetic agents are associated with unwanted and sometimes fatal side effects. There is mounting evidence in support of the efficacy of naturally-occurring phytochemicals possessing anti-inflammatory activity. In this review we discuss key inflammatory pathways associated with colorectal cancer and promising naturally-occurring phytochemicals as anti-inflammatory agents for the prevention and treatment of colorectal cancer.