Gene transfer to the heart is a novel concept that holds great promise both as a therapeutic and an experimental tool. With the advent of improved vector technology and new insights into the pathophysiology of heart failure, it is now possible to target specific intracellular signaling pathways by adenoviral gene transfer. By over or under expressing a specific protein, complex pathways can be probed specifically, and the role of various molecular targets within crucial intracellular pathways can be more precisely defined. This review highlights recent advances made in the field of myocardial gene transfer, with an emphasis on how manipulation of signal transduction pathways by adenoviral gene transfer has been used to elucidate the pathophysiology underlying abnormal cardiac phenotypes that lead to cardiac failure, such as hypertrophy, contractile dysfunction, and apoptosis.