Sepsis represents a life-threatening organ dysfunction due to a compromised host response caused by bacterial and viral infections. Although progress has been made to unravel the underlying pathophysiology, sepsis remains a very serious condition. Adiponectin is an adipokine with multiple beneficial activities relevant to glucose and lipid metabolism whose serum levels are low in obesity and metabolic diseases. In addition, several immunoregulatory activities of adiponectin have been described and circulating adiponectin levels have been positively associated with inflammation in autoimmune diseases such as rheumatoid arthritis and type 1 diabetes. Although an understanding of physiological consequences is still limited, blood adiponectin levels are also elevated in chronic kidney disease and liver cirrhosis, possibly due to impaired biliary and renal excretion. Natriuretic peptides, which increase adiponectin synthesis in adipocytes and are induced in autoimmune diseases and cirrhosis and decreased in obesity, appear to contribute to altered systemic adiponectin levels. In patients with sepsis, data on circulating adiponectin levels are not concordant, probably due to the large diversity in cohorts analyzed, often including patients with a higher risk for severe sepsis due to chronic metabolic disease or other comorbidities. This review article summarizes the main physiological activities of adiponectin and describes its role in inflammation and experimental sepsis. Adiponectin levels obtained in observational studies from serum or plasma of patients with critical illness are discussed. From this analysis, we conclude that circulating adiponectin levels are reduced in sepsis and septic shock, suggesting the potential of adiponectin receptor agonists as an option for sepsis therapy.