Mortality related to sepsis among critically ill patients remains high. Recent literature suggests that hypercapnia may affect the pathophysiology of sepsis. The effects of hypercapnia on sepsis are largely related to the direct effect of hypercapnic acidosis on immune function and, as a consequence, of increased cardiac output that subsequently leads to improved tissue oxygenation. Appropriate management of hypercapnia may aid in improving the outcomes of sepsis. Our aim was to review the effects of compensated hypercapnia and hypercapnic acidosis on sepsis, with a specific focus on critically ill patients. Hypercapnic acidosis has been extensively studied in various in vivo animal models of sepsis and ex vivo studies. Published data from animal experimental studies suggest that the effects of hypercapnic acidosis are variable, with benefit shown in some settings of sepsis and harm in others. The effects may also vary at different time points during the course of sepsis. There are very few clinical studies investigating the effects of hypercapnia in prevention of sepsis and in established sepsis. It appears from these very limited clinical data that hypercapnia may be associated with adverse outcomes. There are no clinical studies investigating clinical outcomes of hypercapnic acidosis or compensated hypercapnia in sepsis and septic shock in critical care settings, thus extrapolation of the experimental results to guide critical care practice is difficult. Clinical studies are needed, especially in critically ill patients, to define the effects of compensated hypercapnia and hypercapnic acidosis that may aid clinicians to improve the outcomes in sepsis.