Lung-protective ventilation (LPV) with low tidal volumes can significantly increase the survival of patients with acute respiratory distress syndrome (ARDS) by limiting ventilator-induced lung injuries. However, one of the main concerns regarding the use of LPV is the risk of developing hypercapnia and respiratory acidosis, which may limit the clinical application of this strategy. This is the reason why different extracorporeal CO2 removal (ECCO2R) techniques and devices have been developed. They include low-flow or high-flow systems that may be performed with dedicated platforms or, alternatively, combined with continuous renal replacement therapy (CRRT). ECCO2R has demonstrated effectiveness in controlling PaCO2 levels, thus allowing LPV in patients with ARDS from different causes, including those affected by Coronavirus disease 2019 (COVID-19). Similarly, the suitability and safety of combined ECCO2R and CRRT (ECCO2R-CRRT), which provides CO2 removal and kidney support simultaneously, have been reported in both retrospective and prospective studies. However, due to the complexity of ARDS patients and the limitations of current evidence, the actual impact of ECCO2R on patient outcome still remains to be defined. In this review, we discuss the main principles of ECCO2R and its clinical application in ARDS patients, in particular looking at clinical experiences of combined ECCO2R-CRRT treatments.