Minimizing toxicity while maximizing efficacy is a common goal in the treatment of any condition but its importance is underscored in the discipline of oncology because of the serious nature of many chemotherapeutic toxicities and the risk of cancer recurrence or disease progression. The challenge of achieving an optimal therapeutic index is especially augmented in the elderly population because of age-related metabolism changes and interacting concurrent medications. Additional factors, such as germline mutations in drug-metabolizing enzymes and other pharmacogenomic alterations, may have more pronounced effects in elderly patients, given their predisposition to altered pharmacokinetics and pharmacodynamics with resulting increased risk of toxicity. Examples of the possible interplay of these factors will be discussed using tamoxifen, paclitaxel, codeine, and fluorouracil as starting points. Limited participation of the elderly in many cancer trials, especially trials assessing drug exposure, makes much knowledge on the interaction of these patient and environmental factors speculative in nature but presents an opportunity for future research to achieve better optimization of chemotherapeutic agents in the elderly.