Antithrombotic drugs are the mainstay of treatment and prevention of thromboembolic disease. The principal risk of antithrombotic therapy is a severe bleeding that requires an appropriate medical intervention. The overall strategy of managing a major bleeding in patients receiving anticoagulants includes the cessation of therapy, as well as an attempt to reverse any remaining antithrombotic effects using, if available, specific antidotes or general procoagulants. In the present review, we discuss the most commonly used anticoagulants, including their mechanisms of action, pharmacokinetics, and side effects, as well as general guidelines for management of major bleeding in patients treated with these drugs. In addition, we describe approaches, currently at the preclinical and clinical study stage, with the potential to improve the safety of anticoagulant therapy in the future. We present an example of the contribution of pharmacists to an increased efficacy and safety of anticoagulant treatments.