Aspirin is being used as an effective analgesic and anti-inflammatory agent at doses >325 mg daily. At low doses (75–325 mg daily), aspirin is the key antiplatelet drug in the pharmacological prevention of cardiovascular diseases. Topical and systemic effects of aspirin in the gastrointestinal mucosa are associated with mucosal damage in the upper and lower gastrointestinal tract. The risk of upper gastrointestinal bleeding with aspirin is increased with old age, male sex, ulcer history and concomitant medication with NSAIDs, cyclooxygenase 2 selective inhibitors, corticosteroids or other antithrombotic agents. In some patients, the cardiovascular benefits of low-dose aspirin might be overcome by the risk of gastrointestinal complications, but withdrawal of aspirin therapy can precipitate a cardiovascular event. These patients will need concomitant therapy with antisecretory agents, especially PPIs, to reduce the gastrointestinal risk. Eradication of Helicobacter pylori infection might be an additional option in patients with a history of ulcer. Furthermore, there is growing evidence that long-term use of aspirin decreases the risk of colorectal cancer, even at low doses. As aspirin is one of the most prescribed drugs worldwide and its clinical impact is huge, physicians need to consider the benefits and harms for each individual patient in order to maximize the benefits of aspirin.