The management of acute coronary syndrome (ACS) has been at the center of an impressive amount of research leading to a significant improvement in outcomes over the last 50 years. The 2020 European Society of Cardiology (ESC) Guidelines for the management of patients presenting without persistent ST-segment elevation myocardial infarction have incorporated the most recent breakthroughs and updates from large randomized controlled trials (RCT) on the diagnosis and management of this disease. The purpose of the present review is to describe the main novelties and the rationale behind these recommendations. Hence, we describe the accumulating evidence against P2Y12 receptors inhibitors pretreatment prior to coronary angiography, the preference for prasugrel as leading P2Y12 inhibitors in the setting of ACS, and the numerous available antithrombotic regimens based on various durations of dual or triple antithrombotic therapy, according to the patient ischemic and bleeding risk profiles. We also detail the recently implemented 0 h/1 h and 0 h/2 h rule in, rule out algorithms and the growing role of computed coronary tomography angiography to rule out ACS in patients at low-to-moderate risk.