Coronary revascularization represents a cornerstone in the treatment of infarct-related cardiogenic shock (CS). Early and effective antithrombotic therapy is critical and has been shown to improve mortality in most patients with acute coronary syndrome. Achieving early effective platelet inhibition and anticoagulation, with minimal risk, is particularly important in those high-risk patients with CS as the mortality remains high at approximately 50%. However, patients with CS are at high risk for both early thrombotic as well as bleeding events and striking the right balance remains a challenge due to a multitude of factors related to drug administration, metabolism and mechanical issues related to therapeutic interventions such as increasing use of mechanical circulatory support (MCS). This review therefore aims to provide an overview of the current practice, the underlying challenges and existing evidence on safety, efficacy and outcomes of adjunctive antiplatelet and antithrombotic therapy in patients with acute myocardial infarction (AMI) complicated by CS and discusses the use of parenteral platelet inhibitors.