The fast cycling of calcium between internal stores and the myofilaments with rapid diffusion down steep concentration gradients provides the cellular basis for cardiac contraction and relaxation. In heart failure, the intracellular Ca2 + dynamics are impaired showing reduced systolic peak Ca2 +, elevated diastolic Ca2 + levels, and prolonged diastolic Ca2 + decay. The recognition that defects in the function of Ca2 + handling proteins are central to the pathogenesis of heart failure has attracted attention to these proteins as potential targets for therapy. Besides pharmacologic interventions including digitalis, ranolazine, levosimendan and others, cardiac gene therapy holds great promise and the recent clinical studies have proven the feasibility of this therapeutic approach. In this review, the rationale underlying modern therapies that modulate intracellular Ca2 + handling for the treatment of human heart failure are presented and discussed.