Precise control of Ca²⁺ movement across the cellular membrane requires specialized transporters such as ion channels, exchangers, and ATP-driven pumps. Plasma membrane calcium pumps (PMCAs) are essential for expulsion of Ca²⁺ from the cell to maintain overall calcium homeostasis and to provide local control of intracellular calcium signaling. Recent work has shown the functional versatility of PMCAs, with specific pumps being required for sperm motility, cochlear hair cell function, signaling feedback in cardiac muscle, and pre- and post-synaptic Ca²⁺ regulation in neurons. The functional versatility of PMCAs is due to differences in their regulation by calmodulin, kinases and other signaling proteins, as well as to their targeting and retention in defined plasma membrane domains. The basis for this is the structural diversity of different PMCAs. In mammals, four genes encode PMCA isoforms 1-4, and each of these has multiple variants due to alternative RNA splicing. The alternatively spliced regions are intimately involved in different regulatory interactions and differential membrane localization of the pumps. For example, alternative splicing generates two major variants of each PMCA (named “a” and “b”) that differ in their 50-100 C-terminal residues. The C-terminal tail acts as auto-inhibitory domain by interacting with the catalytic core of the pump. Binding of calmodulin to this tail releases the inhibition and activates the pump. The degree of inhibition and the kinetics of interaction with calmodulin differ between PMCA splice variants such as PMCA4a and PMCA4b. This translates into functional differences as illustrated by simulations showing how PMCA4a and PMCA4b handle agonist-evoked Ca²⁺ signals. The simulation replicates experimental data obtained in PMCA4a- and PMCA4b-expressing cells [1] and thereby demonstrates how structural diversity provides functional versatility in PMCAs.