There is definitive evidence that iron overload induces oxidative stress and DNA damage, which can enhance carcinogenic risk. However, other evidence suggests that iron deficiency and anemia also increase oxidative stress and DNA damage, which might increase carcinogenesis risk, especially in the gastrointestinal (GI) tract. The aim of this review is to provide essential background information for the accurate interpretation of future research on iron deficiency and increased GI cancer risk. Based on clinical, epidemiological, and experimental evidence, we discuss how iron deficiency might contribute to increased cancer risk through the impairment of several iron-dependent metabolic functions that are related to genome protection and maintenance (e.g., immune responses against cancer-initiated cells, metabolism of toxic compounds, and redox regulation of DNA biosynthesis and repair). Some epidemiological studies have indicated increased risk of GI tumors among individuals with low iron intake or low somatic iron stores, and in vivo data from rodent cancer models indicates the early progression of GI tumors during iron deficiency. Given the preliminary but consistent evidence relating iron deficiency to cancer risk and the fact that iron deficiency affects about one third of the world's population, further studies are needed to define the extent to which iron deficiency might increase GI cancer risk.