Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, complement-mediated hemolytic anemia with protean manifestations. PNH can present as a hemolytic anemia, a form of bone marrow failure, a thrombophilia, or any combination of the above. Terminal complement inhibition is highly effective for treating intravascular hemolysis from PNH and virtually eliminates the risk of thrombosis, but is not effective for treating bone marrow failure. Here, we present a variety of clinical vignettes that highlight the clinical heterogeneity of PNH as well as the attributes and limitations of the two FDA-approved C5 inhibitors (eculizumab and ravulizumab) to treat PNH. We review the concept of pharmacokinetic and pharmacodynamic breakthrough hemolysis and briefly discuss new complement inhibitors upstream of C5 that are in clinical development. Lastly, we discuss the rare indications for bone marrow transplantation in PNH patients.