Ventricular tachycardia in nonischemic heart failure (HF) arises from a nonreentrant mechanism most likely due to delayed afterdepolarizations from activation of a transient inward current (I(ti)). We present data and a paradigm in which an up-regulated Na/Ca exchanger, residual beta-adrenergic responsiveness, and decreased inward rectifying K current (I(K1)) in HF all conspire to markedly increase the propensity for triggered arrhythmias. The up-regulated Na/Ca exchanger plays an additional critical role in unloading the sarcoplasmic reticulum of Ca, thereby causing the mechanical dysfunction. It is imperative that therapeutic approaches for ventricular tachycardia in HF take into consideration cellular Ca handling and excitation-contractile coupling, and their alteration in the failing heart.