The critically ill, asplenic patient presents a variety of management challenges. Historically, the focus of the care of the asplenic population has been the prevention and management of infection, including the often-fatal overwhelming postsplenectomy infection with encapsulated organisms such as Streptococcus pneumoniae. Recently, however, there has been increasing recognition of the spleen’s function in areas outside of immunity because the asplenic state has been identified as a risk factor for such vascular complications as thrombosis and pulmonary hypertension resulting from dysregulated inflammation and coagulation. Because of the relatively small size of this population and the relative infrequency with which critical illness occurs in it, there are few controlled trials that can serve as a basis for therapeutic maneuvers; thus, optimal management requires an astute clinician with an understanding of the pathogenetic mechanisms underlying the reported consequences of splenectomy. The purpose of this review is to explore the pathophysiology of the asplenic state—impairment in adaptive immunity, loss of blood filtration, endothelial dysfunction, and dysregulated coagulation—and how it leads to infection, thrombosis, and pulmonary hypertension as well as to discuss the implications of these conditions on the management of the critically ill, splenectomized patient.