Extracorporeal life support (ECLS) for severe respiratory failure has seen an exponential growth in recent years. Extracorporeal membrane oxygenation (ECMO) and extracorporeal CO2 removal (ECCO2R) represent two modalities that can provide full or partial support of the native lung function, when mechanical ventilation is either unable to achieve sufficient gas exchange to meet metabolic demands, or when its intensity is considered injurious. While the use of ECMO has defined indications in clinical practice, ECCO2R remains a promising technique, whose safety and efficacy are still being investigated. Understanding the physiological principles of gas exchange during respiratory ECLS and the interactions with native gas exchange and haemodynamics are essential for the safe applications of these techniques in clinical practice. In this review, we will present the physiological basis of gas exchange in ECMO and ECCO2R, and the implications of their interaction with native lung function. We will also discuss the rationale for their use in clinical practice, their current advances, and future directions.