The use of extracorporeal life support (ECLS) devices has significantly increased in the last decades. Despite medical and technological advancements, a main challenge in the ECLS field remains the complex interaction between the human body, blood, and artificial materials. Indeed, blood exposure to artificial surfaces generates an unbalanced activation of the coagulation cascade, leading to hemorrhagic and thrombotic events. Over time, several anticoagulation and coatings methods have been introduced to address this problem. This narrative review summarizes trends, advantages, and disadvantages of anticoagulation and coating methods used in the ECLS field. Evidence was collected through a PubMed search and reference scanning. A group of experts was convened to openly discuss the retrieved references. Clinical practice in ECLS is still based on the large use of unfractionated heparin and, as an alternative in case of contraindications, nafamostat mesilate, bivalirudin, and argatroban. Other anticoagulation methods are under investigation, but none is about to enter the clinical routine. From an engineering point of view, material modifications have focused on commercially available biomimetic and biopassive surfaces and on the development of endothelialized surfaces. Biocompatible and bio-hybrid materials not requiring combined systemic anticoagulation should be the future goal, but intense efforts are still required to fulfill this purpose.