Sepsis and acute respiratory distress syndrome (ARDS) constitute devastating conditions with high morbidity and mortality. Sepsis results from abnormal host immune response, with evidence for both pro- and anti-inflammatory activation present from the earliest phases. The “proinflammatory” response predominates initially causing host injury, with later-phase sepsis characterized by immune cell hypofunction and opportunistic superinfection. ARDS is characterized by inflammation and disruption of the alveolar-capillary membrane leading to injury and lung dysfunction. Sepsis is the most common cause of ARDS. Approximately 20% of deaths worldwide in 2017 were due to sepsis, while ARDS occurs in over 10% of all intensive care unit patients and results in a mortality of 30 to 45%. Given the fact that sepsis and ARDS share some-but not all-underlying pathophysiologic injury mechanisms, the lack of specific therapies, and their frequent coexistence in the critically ill, it makes sense to consider therapies for both conditions together. In this article, we will focus on the therapeutic potential of mesenchymal stem/stromal cells (MSCs). MSCs are available from several tissues, including bone marrow, umbilical cord, and adipose tissue. Allogeneic administration is feasible, an important advantage for acute conditions like sepsis or ARDS. They possess diverse mechanisms of action of relevance to sepsis and ARDS, including direct and indirect antibacterial actions, potent effects on the innate and adaptive response, and pro-reparative effects. MSCs can be preactivated thereby potentiating their effects, while the use of their extracellular vesicles can avoid whole cell administration. While early-phase clinical trials suggest safety, considerable challenges exist in moving forward to phase III efficacy studies, and to implementation as a therapy should they prove effective.Thieme. All rights reserved.