Over the last three decades, our knowledge and understanding of the role of phospholamban and its modulation of sarcoplasmic reticulum (SR) function has advanced significantly. Phospholamban is a key regulator of cardiac contractility and modulates SR Ca²⁺ sequestration by inhibiting the SR Ca²⁺ -ATPase (SERCA) in its dephosphorylated state. Upon phosphorylation, which is mediated through β-adrenergic stimulation, the inhibitory effect of phospholamban on the function of SERCA is relieved. This review summarizes recent advances that have been made towards understanding the modulation of SR Ca²⁺-sequestration by phospholamban through the generation and characterization of genetically altered animal models. It also discusses the role of phospholamban in human heart failure and recent attempts to restore SR function in experimentally induced and human heart failure, which may be translated into future therapeutic approaches in the treatment of this disease.