Paroxysmal nocturnal hemoglobinuria (PNH) is a hematological disorder characterized by complement-mediated hemolytic anemia, thrombophilia, and bone marrow failure. PNH is due to a somatic, acquired mutation in the X-linked phosphatidylinositol glycan class A (PIG-A) gene, which impairs the membrane expression on affected blood cells of a number of proteins, including the complement regulators CD55 and CD59. The most evident clinical manifestations of PNH arise from dysregulated complement activation on blood cells; in fact, the hallmark of PNH is chronic, complement-mediated, intravascular hemolysis, which results in anemia, hemoglobinuria, fatigue, and other hemolysis-related disabling symptoms. In addition, the peculiar thromboembolic risk typical of PNH patients is thought as secondary to the complement-mediated hemolysis itself and/or to a complement-mediated activation of platelets. Thus, as a complement-mediated disease, PNH was an appropriate medical condition to develop and to investigate therapeutical complement inhibitors. Indeed, the first complement inhibitor eculizumab, a humanized anti-C5 monoclonal antibody, has been proven safe and effective for the treatment of PNH patients. Chronic treatment with eculizumab results in sustained control of intravascular hemolysis, leading to hemoglobin stabilization and transfusion independence in more than half of the patients. However, recent observations have demonstrated that residual anemia may persist in some patients regardless of sustained fluid-phase terminal complement inhibition. Indeed, persistent dysregulated activation of the early phases of the complement cascade on PNH erythrocytes may lead to progressive C3 deposition on affected cells, which become susceptible to subsequent extravascular hemolysis through the reticuloendothelial system. These findings have renewed the interest for the development of novel complement inhibitors which aim to modulate early phases of complement activation, more specifically at the level of C3 activation. As proof of principle of this concept, an anti-C3 monoclonal antibody has been proven effective in vitro to prevent hemolysis of PNH erythrocytes. More intriguingly, a human fusion protein consisting of the iC3b/ C3d-binding region of complement receptor 2 and of the inhibitory domain of the CAP regulator factor H has been recently shown effective in inhibiting, in vitro, both intravascular hemolysis of and surface C3-deposition on PNH erythrocytes, and is now under investigation in phase 1 clinical trials.