Older adults have an increased burden of comorbidity which increases their risk of being exposed to polypharmacy. Because of underrepresentation of elderly cancer patients in clinical trials, knowledge of the influence of comorbidity and polypharmacy on these patients' response and tolerance to antineoplastic treatment is sparse. We reviewed the literature on comorbidity and polypharmacy in elderly cancer patients and the impact of these factors on treatment outcome. Large population-based studies all found an association between comorbidity and survival among elderly cancer patients. However, we need to focus on cancer-specific survival to conclude on the influence of comorbidity on cancer disease and its treatment. Prospective studies are needed to conclude on the influence of comorbidity and polypharmacy on treatment tolerance and response to antineoplastic treatment.