Despite intensive efforts, the development of novel drugs for the treatment of sepsis has proved to be extremely difficult. A large number of clinical trials have ended in failure. A critical analysis of this record suggests that there is no single reason for these problems. Rather, the explanation lies in part with unexpected failures in the drugs themselves, and in part with the difficulties of trial design in this particular group of patients. In future, trials in this area are likely to be more highly focused, with even stricter protocol definitions to try and ensure a homogeneous patient population.