Critically ill patients often have a low platelet count. A proper identification of the underlying cause of this abnormality is required, because various underlying disorders may necessitate different diagnostic and therapeutic management strategies. Platelets are part of the first line of defense of the body against bleeding, hence, thrombocytopenia may increase the risk of hemorrhage. In case of systemic inflammatory syndromes, such as the response to sepsis, disseminated intravascular platelet activation may occur, which will contribute to microvascular failure and thereby play a role in the development of organ dysfunction. A low platelet count is a strong and independent predictor of an adverse outcome in critically ill patients, thereby facilitating a simple and practical risk assessment in these patients and potentially guiding the use of complex or expensive treatment strategies.