Human heart failure is characterized by distinct alterations in the intracellular homeostasis and key regulators of the sarcoplasmic reticulum Ca2+ sequestration mechanisms. Systolic peak Ca2+ is reduced, diastolic Ca2+ levels are increased and diastolic Ca2+ decay is prolonged. Recently specific changes in the expression, function and modulation of SR Ca2+-ATPase (SERCA) have been elucidated. As such, in a variety of studies SERCA expression appeared to be decreased in the failing human heart, although these findings have been discussed controversially depending on the studied tissue, especially with respect to the non-failing samples and regional variation in the obtained samples. However, consistent findings of a diminished Ca2+ dependent SERCA activation were found. Increasing evidence has been provided that one of the underlying mechanisms for a decreased activation of SERCA is its altered regulation. With respect to this, the modulations through phospholamban and Ca2+-dependent protein kinase II (CaMK II) play a detrimental role in regulating SERCA function. Phospholamban phosphorylation of SERCA at the serine-16 and threonine-17 site is diminished in human heart failure resulting in decreases in the apparent affinity for Ca2+ of the SR Ca2+ uptake rates. In contrast, activation of CaMK II leads to an increased maximal velocity of SR Ca2+ sequestration that may enhance SR Ca2+-load. Additional regulation has been recently elucidated by changes in the apparent coupling ratio of Ca2+ transported per ATP hydrolysed. This review summarizes recent advances in the understanding how SERCA is modulated under physiological and pathophysiological conditions.