During veno-venous extracorporeal membrane oxygenation (V-V ECMO), blood is drained from the central venous circulation to be oxygenated and decarbonated by an artificial lung. It is then reinfused into the right heart and pulmonary circulation where further gas-exchange occurs. Each of these steps is characterized by a peculiar physiology that this manuscript analyses, with the aim of providing bedside tools for clinical care: we begin by describing the factors that affect the efficiency of blood drainage, such as patient and cannulae position, fluid status, cardiac output and ventilatory strategies. We then dig into the complexity of extracorporeal gas-exchange, with particular reference to the effects of extracorporeal blood-flow (ECBF), fraction of delivered oxygen (FdO2) and sweep gas-flow (SGF) on oxygenation and decarbonation. Subsequently, we focus on the reinfusion of arterialized blood into the right heart, highlighting the effects on recirculation and, more importantly, on right ventricular function. The importance and challenges of haemodynamic monitoring during V-V ECMO are also analysed. Finally, we detail the interdependence between extracorporeal circulation, native lung function and mechanical ventilation in providing adequate arterial blood gases while allowing lung rest. In the absence of evidence-based strategies to care for this particular group of patients, clinical practice is underpinned by a sound knowledge of the intricate physiology of V-V ECMO.