Sepsis, currently defined as dysregulated systemic immune response of the host to an infectious insult with subsequent life-threatening organ dysfunction, is a common multifactorial disease. In conjunction with septic shock, the most severe form of sepsis characterized by profound circulatory and metabolic derangement, the two are one of the leading causes of mortality and critical illness worldwide. Despite improvements in the management of sepsis, including timely administration of antibiotic agents, optimization of intravascular volume status and supportive care, no specific treatment exists as of yet. However, an increased understanding of the pathophysiological mechanisms and the biphasic course consisting of pro and anti-inflammatory states, has paved the way for alternative treatment options. Active research has spawned candidate drugs including extracorporal blood purification, immune modulation with corticosteroids, intravenous immunoglobulins, mesenchymal stem cells, GM-CSF, rhIL-7, thymosin-α1 or nanoparticles. Vasopressin-agonists and beta-blocker are agents regulating the cardiovascular system. Promising strategies targeting other organ systems involve novel agents like alkaline phosphatase, thrombomodulin and the gut microbiome. Finally, micronutrients have been assessed as treatment alternatives. However, investigations on new efficient therapy agents are hampered by the broad spectrum of the syndrome, its definition and the heterogeneity of the patients affected. Lacking identification of sepsis subtypes limits the applicability of research results. The outcomes of studies conducted on alternative treatment agents for sepsis and septic shock distance themselves from one-size-fits-all, to focus on individualized medicine including careful treatment timing and clinical pheno- and genotyping. In this context, the mentioned agents are currently of particular interest in treatment for sepsis and give a promising outlook. Therefore, the aim should be stratification of disease and patient to identify who benefits most from therapy.