Studies on thrombus composition in acute stroke or acute myocardial infarction may help elucidate clot etiology and understand reperfusion success or failure. Moreover, such studies may certainly aid in the development of new technologies aimed at retrieving specific subtypes of thrombi; as a matter of fact, thrombus composition is suggested to influence the choice of techniques used during mechanical thrombectomy and plays a role in potential device and thrombus interaction. Over the years, histological analysis on the composition of thrombi causing ischemic stroke has proved to be a powerful tool to set standard prevention and treatment protocols. By isolating clot components, it is possible to provide a more accurate diagnosis and distinguish different stroke subtypes. Studies on histological clot composition support the theory that cryptogenic stroke can have a cardiogenic origin too. Components found in thrombi extracted from stroke patients support the importance of antithrombotic therapy in preventing and treating cerebral ischemia; however, more studies are needed to improve results in all types and subtypes of stroke. Hence, more research is required to further comprehend the role that platelets, fibrin, von Willebrand factor (vWF), and DNA play in relation to mechanical thrombectomy and recombinant tissue plasminogen activator (rtPA) resistance and to overcome certain limitations.