Altered cellular Ca²⁺ handling plays a key role in the pathophysiology of heart failure. A typical aspect of failing heart cells is a decrease in the ability to load Ca²⁺ in SR, which results in a decreased amplitude and a slowed decay rate of Ca²⁺ transients, and an increased diastolic [Ca²⁺]_i. This unloaded SR Ca²⁺ could be ascribed to a decrease in Ca²⁺ re-uptake by SR Ca²⁺ ATPase (SERCA), an increase in Ca²⁺ extrusion by the over-expression of Na⁺/Ca²⁺ exchange (NCX), and an increase in the SR Ca²⁺ leak by the dissociation of FK506-binding proteins (FKBPs) from the SR Ca²⁺ release channel (ryanodine receptors; RyRs). Many inotropic agents including digitalis and ß-receptor agonists have failed to improve long-term prognosis of heart failure in clinical studies. This review introduces newly developed drugs and gene therapies that target SERCA, NCX and RyRs as a possible therapeutic strategy in heart failure. For the SR Ca²⁺ uptake, drugs that enhance SR Ca²⁺ uptake in a cAMP-independent manner, including protein phosphatase inhibitors and MCC-135, are candidates. The SERCA expression and the ablation of phospholamban by gene transfer are also considered. For NCX, the novel specific inhibitors, KB-R7943, SEA0400, and SN-6, and the expression of NCX inhibiting peptide (XIP) would be effective by altering Ca²⁺ flux from the extrusion to outside the cell to the re-uptake to the SR. For RyRs, JTV519 and the over-expression of FKBP12.6 are expected to increase the binding of FKBP12.6 to RyRs hyper-phosphorylated by protein kinase A, and to reduce the SR Ca²⁺ leak. Despite limitations for clinical use, the combination of these agents may restore cellular Ca²⁺ cycling and improve cardiac function with less toxicity.