Context: Sepsis’ s primary therapy consists of antibiotics therapy, supportive therapies, and source control of infection. The failure rate of this approach is about 20-40%. The widespread use of antibiotics has caused multiple drug resistance in primary etiological agents of sepsis in community-acquired and healthcare-associated infections. In the absence of new antibiotic options, alternative treatment modalities seem necessary. Evidence Acquisition: Herein, we have reviewed and discussed current problems with sepsis management and stem cell therapy in sepsis, preclinical, experimental studies, and early-phase clinical trials using stem cells to treat sepsis. In the preparation of the paper, PubMed, Web of Science Core Collection (Clarivate), Scopus, and the web address (www. clinicaltrials. gov) were searched by the keywords (sepsis and cell therapy, septic Shock, and cell therapy). Results: After the inclusion of criteria, we reviewed 301 original articles. Few articles were found for phase II and phase III clinical trials. Eighty-three articles were included in the current review article. Besides problems with infection source control, the host immune response to the infection enumerated for primary underlying pathophysiologic dysregulation of sepsis and complicated the treatment. Mesenchymal stem cells (MSCs) therapy off ers a promising treatment option for sepsis. Indeed, immunomodulatory properties, antimicrobial activity, the capacity of protection against organ failure, enhance the resolution of tissue injury, tissue repair, and restoration after sepsis confer MSCs with a signifi cant advantage to treat the immune and infl ammatory dysfunctions associated with severe sepsis and septic Shock. Conclusions: It seems that MSCs therapy exhibits an appropriate safety index. Future trials should focus on strengthening study quality, reporting MSCs’ therapeutic eff ects and adverse events. Although early clinical trials seem promising and have benefi cial eff ects, we need more controlled clinical studies, especially in phases II and III.