Thrombopoietin (TPO) is a humoral growth factor originally identified for its ability to stimulate the proliferation and differentiation of megakaryocytes. In addition to its actions on thrombopoiesis, TPO directly modulates the homeostatic potential of mature platelets by influencing their response to several stimuli. In particular, TPO does not induce platelet aggregation per se but is able to enhance platelet aggregation in response to different agonists ("priming effect"). Our research group was actively involved, in the last years, in characterizing the effects of TPO in several human critical diseases. In particular, we found that TPO enhances platelet activation and monocyte-platelet interaction in patients with unstable angina, chronic cigarette smokers, and patients with burn injury and burn injury complicated with sepsis. Moreover, we showed that TPO negatively modulates myocardial contractility by stimulating its receptor c-Mpl on cardiomyocytes and the subsequent production of NO, and it mediates the cardiodepressant activity exerted in vitro by serum of septic shock patients by cooperating with TNF-α and IL-1β. This paper will summarize the most recent results obtained by our research group on the pathogenic role of elevated TPO levels in these diseases and discuss them together with other recently published important studies on this topic.