Despite advancements in management of acute myocardial infarction, this disease 
remains one of the leading causes of death. Timely reestablishment of epicardial 
coronary blood flow is the cornerstone of therapy; however, substantial amount 
of damage can occur as a consequence of cardiac ischaemia/reperfusion (I/R) 
injury. It has been previously proposed that the pathway leading to major cell 
death, apoptosis, is responsible for cardiac I/R injury. Nevertheless, there is 
compelling evidence to suggest that necroptosis, a programmed necrosis, 
contributes remarkably to both myocardial injury and microcirculatory 
dysfunction following cardiac I/R injury. Receptor-interacting protein kinase 1 
(RIPK1), RIPK3, and mixed-lineage kinase domain-like pseudokinase (MLKL) are 
shown as the major mediators of necroptosis. In addition to the traditional 
perception that RIPK1/RIPK3/MLKL-dependent plasma membrane rupture is 
fundamental to this process, several RIPK3-related pathways such as endoplasmic 
reticulum stress and mitochondrial fragmentation have also been implicated in 
cardiac I/R injury. In this review, reports from both in vitro and in vivo 
studies regarding the roles of necroptosis and RIPK3-regulated necrosis in 
cardiac I/R injury have been collectively summarized and discussed. Furthermore, 
reports on potential interventions targeting these processes to attenuate 
cardiac I/R insults to the heart have been presented in this review. Future 
investigations adding to the knowledge obtained from these previous studies are 
needed in the pursuit of discovering the most effective pharmacological agent to 
improve cardiac I/R outcomes.