Simple SummaryThe oral mucosa, as part of human mucosa, is an essential part of the oral cavity. It is the first natural barrier against the intrusion of newcomers and a habitat for the oral microbiome. As such, it is receiving ever-increasing interest in clinical and translational research. However, it is in the field of cancer treatment and its toxicity wherein oral mucosa has a prominent role, as oral mucositis is one of the most debilitating cancer treatment complications and a notorious source of worry for oncologists and poor quality of life for cancer patients. This narrative review focuses on the entangled implications of human oral mucosa in cancer and, specifically, in the development of cancer-related oral mucositis support strategies.AbstractThe oral mucosa is a key player in cancer patients and during cancer treatment. The increasing prevalence of cancer and cancer-therapy-associated side effects are behind the major role that oral mucosa plays in oncological patients. Oral mucositis is a debilitating severe complication caused by the early toxicity of chemo and/or radiotherapy that can restrict treatment outcome possibilities, even challenging a patient’s survival. It has been referred to as the most feared cancer treatment complication. Predictive variables as to who will be affected, and to what extent, are still unclear. Additionally, oral mucositis is one of the sources of the increasing economic burden of cancer, not only for patients and their families but also for institutions and governments. All efforts should be implemented in the search for new approaches to minimize the apparently ineluctable outburst of oral mucositis during cancer treatment. New perspectives derived from different approaches to explaining the interrelation between oral mucositis and the oral microbiome or the similarities with genitourinary mucosa may help elucidate the biomolecular pathways and mechanisms behind oral mucosa cancer-therapy-related toxicity, and what is more important is its management in order to minimize treatment side effects and provide enhanced cancer support.