Colorectal cancer (CRC) is the most common gastrointestinal cancer and mainly a disease of high-income countries that follow a Western lifestyle. The majority of CRC cases are sporadic and caused by accumulated genetic mutations in the intestinal epithelium in response to detrimental environmental factors (e.g., diet, lifestyle). A high intake of dietary fiber is linked to low CRC risk, whereas the consumption of red meat and animal fat is associated with a higher CRC risk. Recent evidence indicates that the gut microbiota affects CRC risk and colonic tumorigenesis in humans: specific bacterial virulence factors or toxins show tumor-promoting effects and a disturbed composition of the gut microbiota with lower microbial diversity (“dysbiosis”) is associated with higher CRC risk and identified in fecal samples of CRC patients. Interactions of gut bacteria with host-derived or dietary factors may result in metabolites that have tumor-promoting or genotoxic effects in the colon (e.g., secondary bile acids, hydrogen sulfide, reactive oxygen species, N-nitroso compounds). In contrast, diet-mediated changes were also demonstrated to have tumor-suppressive activity: the fermentation of dietary fiber by gut bacteria results in short-chain fatty acids (SCFA), in particular butyrate, that have tumor-suppressive and anti-inflammatory properties. Given the role of diet in CRC risk, increasing the intake of dietary fiber and moderating red meat and animal fat consumption seems to be promising for CRC prevention. In addition, early detection of precancerous polyps by endoscopic screening of the colon and new non-invasive fecal screening tests can help to reduce CRC incidence. Finally, advances in minimally invasive surgery and novel targeted therapies can improve CRC therapy. In conclusion, addressing and mitigating the risk factors complemented by a diligent screening strategy will help to decrease the incidence of CRC.