50% of mortalities attributable to cardiac causes are accounted for by cardiac arrhythmias occurring either independently or as a result of other underlying heart diseases. Classic pharmacological antiarrhythmic approaches suffer from poor efficacy and risk of serious complications. Recently, the notion of “upstream therapy”, targeting the processes involved in the development of arrhythmic substrates, has increasingly become the focus of attention. This talk will overview our recent research by using genetically modified mouse models to investigate the potential roles of several intracellular signalling proteins, particularly, mitogen-activated protein kinase kinse 4 (MKK4) and P21-activated kinase1 (Pak1), in atrial and ventricular arrhythmias associated with ageing and stress. For example, in our newly developed mouse model with atrial cardiomyocyte-specific deletion of mkk4 (MKK4ACKO), with age, MKK4ACKO mice became more susceptible to atrial arrhythmias with characteristic slow atrial conduction comparing with control MKK4F/F mice. In parallel, an increased interstitial fibrosis, up-regulated TGF-β1 signalling and dysregulation of matrix metalloproteinases and their inhibitory enzymes were observed in the atrium of MKK4ACKO mice in contrast to control mice. The results for the first time have determined a critical role of MKK4 in age-related atrial structural remodelling associated with atrial fibrillation. In summary, our research provides new insights into exploring upstream therapeutic targets for treating cardiac arrhythmias. Where applicable, the authors confirm that the experiments described here conform with The Physiological Society ethical requirements.