Late-life depression is very common and is associated with high rates of morbidity and mortality. While the field of geriatric psychiatry is focused on depression treatment, prevention is an enticing option. Prevention of late-life depression would decrease both emotional suffering and depression-associated morbidity and mortality and may decrease dependence on non-mental health professionals to detect depression and to initiate a treatment referral. This paper will review current thinking on prevention research with a particular focus on its application to late-life depression. To illustrate these issues, we discuss recent and ongoing clinical trials of interventions to prevent depression in two populations of older persons: those with age-related macular degeneration (AMD) and those with cerebrovascular disease.