Ca²⁺ is a central player in the excitation-contraction coupling of cardiac myocytes, the process that enables the heart to contract and relax. Mishandling of Ca²⁺ is a central cause of both contractile dysfunction and arrhythmias in pathophysiological conditions such as heart failure (HF). Upon electrical excitation, Ca²⁺ enters the myocytes via voltage-gated Ca²⁺ channels and induces further Ca²⁺ release from the sarcoplasmic reticulum (SR). This raises the free intracellular Ca²⁺ concentration ([Ca²⁺]_i), activating contraction. Relaxation is driven by [Ca²⁺]_i decline, mainly due to re-uptake into the SR via SR Ca²⁺-ATPase and extrusion via the sarcolemmal Na⁺/Ca²⁺ exchange, NCX. Intracellular Na⁺ concentration ([Na⁺]_i) is a main regulator of NCX, and thus [Na⁺]_i plays an important role in controlling the cytosolic and SR [Ca²⁺]. [Na⁺]_i may have an even more important role in HF because NCX is generally upregulated. There are several pathways for Na⁺ entry into the cells, whereas the Na⁺/K⁺ pump (NKA) is the main Na⁺ extrusion pathway and therefore is essential in maintaining the transmembrane Na⁺ gradient. Phospholemman is an important regulator of NKA function (decreasing [Na⁺]_i affinity unless it is phosphorylated). Here we discuss the interplay between Ca²⁺ and Na⁺ in myocytes from normal and failing hearts.