Background and Objectives While evidence in support of aspirin use in secondary prevention is well documented, the role of aspirin in primary prevention remains unclear. We conducted a systematic literature review to evaluate aspirin use in cardiovascular disease (CVD) and cancer primary prevention, and consider whether aspirin’s role is set to become more clearly defined based on past and prospective studies. Data Sources Utilizing PubMed, the reviewers identified appropriate Medical Subject Headings (MeSH) terms to establish CVD-based studies, cancer-based studies, and studies on adherence. Study Eligibility Criteria Date restrictions of May 31, 2008 to May 31, 2013 were applied to capture the most robust meta-analyses and randomized controlled trials. Websites of relevant EU and US scientific societies were used to identify the key guidelines for aspirin use in primary prevention of CVD, and ClinicalTrials.gov was used to establish future or ongoing trials. Results Evidence in support of aspirin prophylaxis is conflicting, though some meta-analyses have underlined potential benefit in reducing cardiovascular events. Despite this apparent benefit, bleeding risk with aspirin is consistently higher versus control, and remains a concern. A reduction of cancer incidence and mortality after a least 3 and 5 years treatment, respectively, is also apparent with aspirin. Conclusion Available data on aspirin in primary prevention suggest a modest benefit for patients at high risk of CVD, and a promising benefit for those at risk of cancer. Future studies should help to elucidate whether the benefit of aspirin outweighs risk in appropriate patient groups.