The regulation of intracellular [Ca²⁺]_i is important for all cells, but in particular for smooth muscle, as [Ca²⁺]_i is a key second messenger leading to contraction. Mechanisms for the cellular clearance of [Ca²⁺]_i form one side of Ca²⁺ homeostasis and include: Plasma Membrane Ca²⁺ ATPases (PMCA), Sarcoplasmic/Endoplasmic Reticulum Ca²⁺ ATPases (SERCA), Na⁺-Ca²⁺-exchangers (NCX) when coupled to the Na⁺-K⁺ ATPases (NKA) and in some cases mitochondria. The nature and relative contribution of these various components of cytosolic Ca²⁺ clearance have long been an important topic for study in smooth muscle, particularly as related to regulation of contractility. These studies have largely depended on inhibition of the various components. Recently advances in gene-targeting and transgenesis have made it possible to add or delete individual components, and importantly specific isoforms from the cell. In this brief review, we will focus on new information on Ca²⁺ clearance in smooth muscle gained from studies on gene-altered mice models. These provide a deeper understanding of distinct functional roles for individual isoforms and the interactions between various components.