Intramucosal acidosis, that it is to say, an increased intramucosal-arterial PCO₂ difference, is a common finding in clinical and experimental sepsis. Nevertheless, the physiologic significance of increases in tissue PCO₂ is controversial, since CO₂ can be generated by both aerobic and anaerobic biochemical processes. PCO₂ can rise after buffering of protons produced in the hydrolysis of high-energy phosphate compounds by bicarbonate, or after the anaerobic production of acids, like lactate. In this case, it could represent tissue dysoxia. Alternatively, an increase in tissue PCO₂ could denote hypoperfusion and diminished removal of the CO₂ produced during the oxidation of pyruvate. In this last situation, aerobic metabolism might be preserved. In the present review, we discuss the physiologic mechanisms that determine tissue and venous hypercarbia during the three classic forms of hypoxia: stagnant, hypoxic and anemic hypoxia. The results of experimental studies suggest that tissue minus arterial and venoarterial PCO₂ gradients primarily reflect alterations in tissue perfusion. These conclusions are further confirmed by a mathematical model of CO₂ transport. In sepsis, however, tissue hypercarbia might develop despite normal or high cardiac output. This phenomenon has been initially interpreted as secondary to alterations in energetic metabolism, the so-called cytopathic hypoxia. Yet, new evidences show that the underlying mechanism to tissue hypercarbia in sepsis might be due to severe microcirculatory derangements. In summary, experimental results support the hypothesis that increases in tissue and venous CO₂ are insensitive markers of tissue dysoxia, and merely reflect vascular hypoperfusion.