Despite the development of a wide range of therapies, heart failure remains a leading cause of death in Western society. New therapies are needed to help combat this debilitating condition. Exercise is becoming an increasingly important feature of rehabilitation programmes for patients with heart failure. Before the 1980s, patients with heart failure were advised not to exercise as it was thought that exercise would increase the risk of a cardiac event (such as myocardial infarction). However, in recent years both aerobic and resistance training have been shown to be safe and beneficial for patients with heart failure, improving exercise tolerance and quality of life, and preventing muscular deconditioning. The molecular mechanisms responsible for exercise-induced cardioprotection are yet to be elucidated, however studies in transgenic mice have identified PI3K(p110α) (phosphoinositide 3-kinase p110α) as a likely mediator. PI3K(p110α) is a lipid kinase which is activated in the heart during chronic exercise training, and is important for maintaining heart structure and function in various pathological settings. In the present review the protective effects of PI3K(p110α) in the failing heart and its potential as a therapeutic strategy for the treatment of heart failure is discussed.