Proper contractile function of the heart depends on intact excitation–contraction processes and ion homeostasis of the myocytes. The Ca²⁺ ion activates contraction through its binding to troponin C. However, Ca²⁺ homeostasis is tightly linked to Na⁺ regulation because the primary mechanism for Ca²⁺ efflux in cardiac myocytes is via electrogenic Na⁺/Ca²⁺-exchange. While altered Ca²⁺-homeostasis has been demonstrated in animal models of heart failure and failing human cardiac tissue, the role of dysfunctional Na⁺ handling processes in altered excitation–contraction coupling remains obscure. Furthermore, altered Na⁺ handling has been implicated in a wide range of cellular processes, such as regulation of membrane potential, pH, and growth. This review will discuss (1) the evidence for altered [Na⁺]_i homeostasis in the failing human heart, (2) how alterations in the Na⁺ electrochemical gradient can influence Ca²⁺ handling, contractile function, and a number of other cellular processes, and (3) the potential defects in Na⁺ channels and transporters that may underlie altered [Na⁺]_i in the failing human heart.