Older adults often have multiple chronic conditions that may decrease additional life expectancy. Research evaluating the benefits and harms of screening must include consideration of competing morbidities and patient heterogeneity (beyond age), potentially increased harms of screening, and patient preferences. Other areas in need of additional research include the lack of evidence for older adults on the harms of screening tests; the overdiagnosis of disease; the burden of disease labeling; the effects of inaccurate test results; the harms of disease treatment; and harms related to prioritization of healthcare (e.g., for a particular patient, lifestyle counseling may be more important than screening). Nontraditional outcomes, such as the effects on family caregivers, are also relevant. Studies comparing trajectories of quality-adjusted survival with and without screening to assess net benefit are typically lacking. There is little evidence on the preferences of older adults for deciding whether to be screened, the process of being screened, and the health states associated with being or not being screened. To enhance the quality and quantity of evidence, older adults need to be enrolled in screening trials and clinical studies. Measures of functional status and health-related quality of life (HRQL) need to be included in trials, registries, and cohort studies. This article addresses these challenges, and presents a framework for what research is needed to better inform screening decisions in older adults.