There are many anti-neoplastic agents in cancer treatment. Combination regimens are often the main standard treatment, particularly for gastrointestinal malignancies. The introduction of new regimens that combine fluoropyrimidines with irinotecan or oxaliplatin and recently also with antibodies against the Epidermal Growth Factor Receptor (EGFR) (cetuximab and panitumumab) and against the Vascular Endothelial Growth Factor (VEGF) (bevacizumab) pathways, has dramatically improved the progression free survival and survival of patients with metastatic colorectal cancer. This rapid extension of available anti-neoplastic drugs has, however, also highlighted the urgent need for clinicians to better understand and identify the spectrum of acute and late toxicities of these drugs. Acute and long-term adverse effects are inherent to non-surgical cancer treatment using chemotherapy and/or radiation therapy, which can profoundly affect the gastrointestinal tract leading to a wide spectrum of acute and late toxicities. An improved knowledge of the aetiology, incidence, supportive measures and of the prevention of these toxicities is warranted to improve patient care. We herein review and discuss the main acute and late gastrointestinal toxicities of chemotherapy and/or radiotherapy for patients with gastrointestinal malignancies.