Infective endocarditis (IE) is a thromboinflammatory disease of the endocardium, with pathophysiology mostly the result of the interplay between microorganisms and modifiers of the hemostasis system. In this setting, the evidence gathered so far warrants a more systematic appraisal. In this review article, experimental and clinical data on the role of hemostasis in IE are summarized. Starting from the current pathogenetic model of IE, we discuss the dual role of platelets in this condition, the microbial interaction with the hemostasis system, also describing nonspecific hemostasis changes during sepsis. We finally propose our hypothesis of thrombophilia as a possible trigger of IE, highlighting the challenges that the study of hemostasis in IE presents. The role of hemostasis in IE appears to be an exciting field of research. The activity of the hemostasis system is highly relevant in terms of susceptibility, progression, and treatment of IE. Pharmacologic modulation of hemostasis before and after IE onset is possible and represents still a largely unexplored area of study.