While the anticancer effect of omega-3 polyunsaturated fatty acids (omega-3 fatty acids), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has been the subject of intense study, our understanding regarding the underlying mechanisms of omega-3 fatty acids against cancer is still limited. Recent studies describing the cancer protective effect of EPA and DHA have sparked a renewed interest in using these fatty acids for cancer prevention and treatment. Here, we summarize the significance of omega- 3 fatty acids in the initiation and progression of cancer, and review the complex mechanisms by which EPA and DHA are thought to have anticancer activities during cancer development. It is concluded that omega-3 fatty acids may exert their anticancer actions by influencing multiple targets implicated in various stages of cancer development, including cell proliferation, cell survival, angiogenesis, inflammation, metastasis and epigenetic abnormalities that are crucial to the onset and progression of cancer.