Platelet dysfunction is commonly acquired due to medications, procedures, medical conditions, and underlying hematologic disease. These issues are presented, the data reviewed, and recommendations given herein. Many medications and dietary supplements have platelet-inhibitory effects in vitro, although the clinical effects on bleeding risks are unclear for many. Platelet-inhibitory drugs are key in the treatment of vascular disease. Data are available to aid in the management of these medications to prevent hemorrhagic complications. Bleeding in patients with renal failure has decreased with improved dialysis and the use of erythropoietin, but remains a challenge. Platelet dysfunction accompanies cardiac valvular disease and use of cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation. Hematologic disorders including myeloproliferative disorders (MPDs), myelodysplasia, paraproteinemias, and immune thrombocytopenia (ITP) can also be associated with hemorrhagic complications due to platelet dysfunction. Knowledge of which factors affect bleeding risk and how to treat individuals with acquired platelet dysfunction are important in optimizing patient care.