Complement is an elaborate system of innate immunity. Genetic variants and 
autoantibodies leading to excessive complement activation are implicated in a 
variety of human diseases. Among them, the hematologic disease paroxysmal 
nocturnal hemoglobinuria (PNH) remains the prototypic model of complement 
activation and inhibition. Eculizumab, the first-in-class complement inhibitor, 
was approved for PNH in 2007. Addressing some of the unmet needs, a long-acting 
C5 inhibitor, ravulizumab, and a C3 inhibitor, pegcetacoplan, have also now been 
approved for PNH. Novel agents, such as factor B and factor D inhibitors, are 
under study, with very promising results. In this era of several approved 
targeted complement therapeutics, selection of the proper drug must be based on 
a personalized approach. Beyond PNH, complement inhibition has also shown 
efficacy and safety in cold agglutinin disease, primarily with the C1s inhibitor 
of the classical complement pathway sutimlimab, as well as with pegcetacoplan. 
Furthermore, C5 inhibition with eculizumab and ravulizumab, as well as 
inhibition of the lectin pathway with narsoplimab, is being investigated in 
transplantation-associated thrombotic microangiopathy. With this revolution of 
next-generation complement therapeutics, additional hematologic entities, such 
as delayed hemolytic transfusion reaction or immune thrombocytopenia, might also 
benefit from complement inhibitors. Therefore, this review aims to describe 
state-of-the-art knowledge of targeting complement in hematologic diseases, 
focusing on (1) complement biology for the clinician, (2) complement activation 
and therapeutic inhibition in prototypic complement-mediated hematologic 
diseases, (3) hematologic entities under investigation for complement 
inhibition, and (4) other complement-related disorders of potential interest to 
hematologists.