Patients with incurable cancers have an increasing number of comorbidities, which can lead to polypharmacy and its associated adverse events (drug-to-drug interaction, prescription of a potentially inappropriate medication, adverse drug event). Deprescribing is a patient-centered process aimed at optimizing patient outcomes by discontinuing medication(s) deemed no longer necessary or potentially inappropriate. Improved patient quality of life, risk reduction of side effects or worse clinical outcomes, and a decrease in healthcare costs are well-documented benefits of deprescribing. Deprescribing and advance care planning both require consideration of patients’ values, preferences, and care goals. Here, we provide an overview of comorbidities and associated polypharmacy risks in cancer patients, as well as useful tools and resources for deprescribing in daily practice, and we shed light on how deprescribing can facilitate advance care planning discussions with patients who have advanced cancer or a limited life expectancy.