Cancer treatments have been key to improve survivorship of patients affected by this dreadful disease. Among these, cytotoxic chemotherapy and, in recent years, immunotherapy are extensively used. However, these pharmacological treatments are aggressive not only to the tumor cells but also to many other cells in the body, particularly those that have a high proliferative ratio, like epithelial cells in the gastrointestinal mucosa, causing mucositis from mouth to anus. Although mucositis may partly underlie the most feared gastrointestinal adverse effects of cancer chemotherapy, such as nausea and vomiting, constipation, diarrhea, bloating, and abdominal pain, other mechanisms, including direct or indirect (inflammation-derived) neurotoxicity affecting the enteric nervous system (enteric neuropathy), and dysbiosis (altered gastrointestinal microbiota) have more recently demonstrated to also play a very relevant role. Although immunotherapy has increased the selectivity against cancer cells, thus making treatment safer, this type of therapy has been demonstrated to cause immune-related adverse events that may also affect the digestive system. Some strategies may reduce the occurrence and severity of the gastrointestinal short- and long-term adverse effects caused by conventional antineoplastic drugs and the new immunotherapies, but these strategies are not always useful and may also produce their own side effects. With increasing rates of cancer incidence, prevalence, and survivorship, there is an urgent need to find new, more efficient, and safer strategies, able to reduce the impact of cancer therapy. This chapter focuses on the gastrointestinal adverse effects caused by pharmacological cancer therapies (chemo- and immunotherapy), their mechanisms of action, and their management.