Publisher Summary Understanding cardiac contractility is essential for advances in the treatment of cardiac diseases, particularly heart failure. Recently several lines of transgenic mice have been developed in which β -adrenergic receptor ( β AR) signaling has been altered. Manipulation of various components of the myocardial β AR system has increased the understanding of cardiovascular diseases, such as heart failure, in which adrenergic signaling plays a critical role. Probably the most important receptors involved in beat-to-beat cardiac regulation are the adrenergic receptors. Myocardial β ARs, for example, mediate increases in heart rate and contractility in response to increases in sympathetic neurotransmission. Despite significant advances in the understanding of β AR signaling in heart failure, it remains to be determined whether changes in β AR function can directly promote deterioration of heart function or are just secondary phenomena resulting as a consequence of enhanced local and systemic circulating catecholamines. Transgenic technology has made it possible to target adrenergic signaling components directly to the heart. The targeted overexpression of these molecules provides a powerful approach to understand how molecular alterations, which are known to occur in a disease, can modify the physiological phenotype. Several of these transgenic models are discussed in this chapter. To determine whether increasing the number of receptors would lead to greater G-protein coupling, transgenic mice have been generated by overexpressing the human β 2 AR. The murine α -myosin heavy chain ( α -MyHC) gene promoter is utilized to specifically target β 2 AR to the myocardium. Surprisingly, cardiac β AR signaling in these animals has been maximal even in the absence of exogenous agonist, as assessed by the measurement of several biochemical and physiological parameters. Baseline membrane adenylyl cyclase activity from transgenic hearts was increased twofold over baseline activity. Monitoring the physiological phenotype in these models is likely to provide an extremely powerful approach to the understanding of disease processes where normal regulatory mechanisms have failed.