The elderly frequently have changes in pharmacokinetics, sensitivity to medications, homeostatic reserve (ability to tolerate physiological challenges), exposure to multiple medications, and adherence. All of these age-associated factors can potentially influence total exposure to medication, adverse effects, and subsequent treatment outcome. Most clinical trials are performed with healthy, younger adults. Extrapolating the results of these trials to the elderly may be inappropriate, particularly for the antidepressant treatment of depression. The authors review these age-associated differences and discuss their implications for antidepressant use in older adults.