Aging is associated with polymorbidity and polypharmacy. In the absence of a consensual definition, polypharmacy has been defined according to the number of drugs that an individual takes or to the presence of the risk of at least one severe drug interaction. In older cancer patients, polypharmacy is at least as common as it is in individuals of the same age without cancer. The management of cancer itself may result in the addition of more medications to counteract the adverse effects of antineoplastic treatment. Polypharmacy may be necessary to control the multiple health conditions of the older person, but it may represent a risk factor for more complications from antineoplastic therapy, and it may affect the outcome of cancer treatment. Polypharmacy is also associated with increased cost. The criteria proposed for the management of polypharmacy include the assessment that all medical conditions are properly treated, the avoidance of drug interactions, and of drugs that may compromise the outcome of antineoplastic treatment and the choice of drugs with the lowest risk of complications in older individuals.