BACKGROUND/OBJECTIVES: Few studies have rigorously examined the magnitude of changes in well-being after a transition into sustained and substantial caregiving, especially in population-based studies, compared with matched noncaregiving controls. DESIGN: We identified individuals from a national epidemiological investigation who transitioned into caregiving over a 10- to 13-year follow-up and provided continuous in-home care for at least 18 months and at least 5 hours per week. Individuals who did not become caregivers were individually matched with caregivers on age, sex, race, education, marital status, self-rated health, and history of cardiovascular disease at baseline. Both groups were assessed at baseline and follow-up. SETTING: REasons for Geographic And Racial Differences in Stroke study. PARTICIPANTS: A total of 251 incident caregivers and 251 matched controls. MEASUREMENTS: Perceived Stress Scale (PSS), 10-Item Center for Epidemiological Studies-Depression (CES-D), and 12-item Short-Form Health Survey quality-of-life mental (MCS) and physical (PCS) component scores. RESULTS: Caregivers showed significantly greater worsening in PSS, CES-D, and MCS, with standardized effect sizes ranging from 0.676 to 0.796 compared with changes in noncaregivers. A significant but smaller effect size was found for worsening PCS in caregivers (0.242). Taking on sustained caregiving was associated with almost a tripling of increased risk of transitioning to clinically significant depressive symptoms at follow-up. Effects were not moderated by race, sex, or relationship to care recipient, but younger caregivers showed greater increases in CES-D than older caregivers. CONCLUSION: Persons who began substantial, sustained family caregiving had marked worsening of psychological well-being, and relatively smaller worsening of self-reported physical health, compared with carefully matched noncaregivers. Previous estimates of effect sizes on caregiver well-being have had serious limitations due to use of convenience sampling and cross-sectional comparisons. Researchers, public policy makers, and clinicians should note these strong effects, and caregiver assessment and service provision for psychological well-being deserve increased priority.