Cardiovascular pathologies are an enormous burden in human health and despite the vast amount of research; the molecular mechanisms and pathways that control the underlying pathologies are still not fully appreciated. The Janus kinase (JAK)–signal transducers and activators of transcription (STAT) pathway has recently been shown to be an integral part of the response of the myocardium to various cardiac insults, including myocardial infarction, oxidative damage, myocarditis, hypertrophy and remodeling, in addition to having a prominent role in cardioprotective therapies such as ischaemic preconditioning. Here, recent advances in the understanding of how the JAK–STAT pathway orchestrates the response to cellular damage in the myocardium are discussed, along with the potential benefits and challenges in manipulating this pathway in cardiovascular therapy.