Heart failure is a common and complex clinical syndrome characterized by progressive ventricular dilatation, depressed contractile function and premature death. Abnormalities in the beta-adrenergic receptor (betaAR) signaling such as betaAR down-regulation and desensitization are hallmarks of heart failure. Results from previous studies suggest that chronic betaAR dysfunction in the failing heart is maladaptive and contributes to the deterioration in cardiac function. In this review we will discuss a number of recent studies on betaAR signaling and addressing the role of phosphoinositide-3 kinase (PI3K) in the development of betaAR dysfunction and the progression of heart failure. Novel possible strategies to ameliorate cardiac dysfunction in heart failure through the competitive inhibition of PI3K are also described.