Perioperative management of patients who are receiving anticoagulant or antiplatelet drugs and require surgical or invasive procedure is a dilemma for clinicians. The discontinuation exposes the patient to an exceedingly high risk of thromboembolism while there is an exceedingly high bleeding risk if antithrombotic therapy is continued, strictly related to the type of surgery. This complex management is based on the assessment of thromboembolic and bleeding risk. In this review we analyze the strategies to optimize the perioperative use of antithrombotic drugs with special attention to new oral anticoagulant drugs, also in cancer patients.