There is currently little data showing that older adults can derive benefit from cancer screening. Advancing age is associated with an increasing prevalence of cancer and other chronic conditions, or comorbidity, and questions remain about the interactions between comorbidity and cancer screening in the elderly population. In this Review, we assess the available evidence on the effects of comorbidity on cancer screening in elderly individuals. In view of the high heterogeneity of existing data, consistent recommendations cannot be made. Decisions on cancer screening in older adults should be based on an appropriate assessment of each individual’s health status and life expectancy, the benefits and harms of screening procedures, and patient preferences. We suggest that Comprehensive Geriatric Assessment might be a necessary step to identify candidates for cancer screening in the elderly population. Specific clinical trials should be done to improve the evidence and show the effectiveness and cost-effectiveness of cancer screening in older adults.