The venous-to-arterial carbon dioxide difference [P(v-a)CO2] was calculated from the difference of venous CO2 and arterial CO2, which has been used to reflect the global flow in the circulatory shock. Moreover, recent clinical studies found the P(v-a)CO2 was related to the sublingual microcirculation perfusion in the sepsis. However, it is still controversial that whether P(v-a)CO2 could be used to assess the microcirculatory flow in septic patients. Moreover, the related influent factors should be taken into account when interpreting P(v-a)CO2 in clinical practice. This paper reviews the relevant experimental and clinical scenarios of P(v-a)CO2 with the aim to help intensivists to use this parameter in the resuscitation of septic shock patients. Furthermore, we propose a conceptual framework to manage a high P(v-a)CO2 value in the resuscitation of septic shock. The triggers of correcting an elevated P(v-a)CO2 should take into consideration the other tissue perfusion parameters. Additionally, more evidence is required to validate that a decreasing in P(v-a)CO2 by increasing cardiac output would result in improvement of microcirculation. Further investigations are necessary to clarify the relationship between P(v-a)CO2 and microcirculation.