Heart failure affects approximately 2.4% of the adult population in Western society and 11% of people over the age of 80 years old. The prevalence of symptomatic heart failure is increasing due to a growing ageing population. Existing therapies typically slow, rather than prevent or reverse heart failure progression. Furthermore, therapeutics that are effective often have side effects. Thus, new well-tolerated therapies with the ability to significantly attenuate adverse cardiac remodelling and improve function of the failing heart are greatly needed. Identification of the molecular distinction between pathological (detrimental) and physiological (normal) cardiac growth or hypertrophy has provided a new avenue for tackling this problem. Pathological and physiological hypertrophy are mediated by distinct signalling cascades, and previous studies in our laboratory have shown that the insulin-like growth factor 1 (IGF-1)-phosphoinositide 3-kinase (PI3K) pathway plays a critical role for the induction of exercise-induced physiological hypertrophy and provides cardiac protection. Subsequently, using genetically modified PI3K mouse models, we have identified a cohort of microRNAs that are regulated by the PI3K(p110α) pathway and correlate with cardiac function. microRNAs are short (~22 nucleotides), non-coding RNA molecules involved in a range of biological processes. They represent attractive therapeutic targets because they can be efficiently inhibited in vivo. My recent studies demonstrate that inhibition of the PI3K(p110α)-regulated microRNA-34 family, using locked nucleic acid (LNA) antimiRs (i.e. microRNA inhibitors) in a mouse model of pressure overload improved cardiac function, decreased cardiac hypertrophy and attenuated lung congestion and atrial enlargement. This was associated with reduced cardiac fibrosis and decreased cardiac stress gene expression, improved angiogenesis and upregulation of several direct microRNA-34 targets. Thus, targeting microRNAs regulated by PI3K(p110α) may represent a novel therapeutic strategy to treat heart failure.