Since its introduction in the clinic, the first complement inhibitor eculizumab has changed the paradigm of PNH treatment. However, a ten-year experience has also taught us that there are same pitfalls which represent a challenge to improve the current anti-complement treatment. The most obvious unmet clinical need remain residual anemia, because one third of patients remains transfusion-dependent, and an additional third still lives with moderate anemia. It has been demonstrated that uncontrolled activation of early steps of the complement plays a major role in this reduced clinical benefit, making C3-mediated extravascular hemolysis the next challenge of PNH treatment. Indeed, a number of novel complement therapeutics is currently under investigation. Novel anti-C5 agents exploiting different technologies of drug design are available; likely they parallel the safety and efficacy profile of eculizumab. However, there is a growing interest for agents which target early phases of complement activation, since they may result in clinical benefit by preventing C3-mediated extravascular hemolysis. These second-generation complement inhibitors include anti-C3 agents, which have as lead compound compstatin and its derivatives, as well as some inhibitors of the alternative pathway, which specifically target complement factor B and D. Here we review the plethora of preclinical data, and the few clinical experiences that will hopefully change in the near future the scenario of anti-complement treatment in PNH, leading to improved clinical outcome.