The biochemical function of the plasma membrane calcium ATPases (PMCAs) is the extrusion of cytosolic Ca²⁺ from the cell. Although this general function is well documented, the role of the complex isoform diversity and especially the contribution of specific isoforms to pathological conditions is less well understood. No human disease has been linked to a defect in any of the four PMCA genes. Nevertheless, isoforms do not have redundant functions, as shown by the indispensable role of PMCA2 demonstrated in transgenic mice. This review summarizes the results of recent analysis of the PMCA dysregulation in diseased cells or model systems of pathological conditions, including both acute disorders like hypoxia/ischemia and seizure, and slowly progressing dysfunctions like Alzheimer's disease, hypertension, diabetes and aging. Abnormalities in PMCA or its regulators have been described in various organs, reflected in changes of expression levels or in modifications or proteolysis of the PMCA protein. Changes of PMCA function are often detected in cell types different from the specific type involved in the pathology, pointing to more general defects. Examples are erythrocytes in diabetes and blood platelets in hypertension. The changes suggest the significance of PMCA in Ca²⁺ homeostasis both in excitable and non-excitable cells.