Ca(2+) is a major signaling molecule in both excitable and non-excitable cells, where it serves critical functions ranging from cell growth to differentiation to cell death. The physiological functions of these cells are tightly regulated in response to changes in cytosolic Ca(2+) that is achieved by the activation of several plasma membrane (PM) Ca(2+) channels as well as release of Ca(2+) from the internal stores. One such channel is referred to as store-operated Ca(2+) channel that is activated by the release of endoplasmic reticulum (ER) Ca(2+) which initiates store-operated Ca(2+) entry (SOCE). Recent advances in the field suggest that some members of TRPCs and Orai channels function as SOCE channels. However, the molecular mechanisms that regulate channel activity and the exact nature of where these channels are assembled and regulated remain elusive. Research from several laboratories has demonstrated that key proteins involved in Ca(2+) signaling are localized in discrete PM lipid rafts/caveolar microdomains. Lipid rafts are cholesterol and sphingolipid-enriched microdomains that function as unique signal transduction platforms. In addition lipid rafts are dynamic in nature which tends to scaffold certain signaling molecules while excluding others. By such spatial segregation, lipid rafts not only provide a favorable environment for intra-molecular cross-talk but also aid to expedite the signal relay. Importantly, Ca(2+) signaling is shown to initiate from these lipid raft microdomains. Clustering of Ca(2+) channels and their regulators in such microdomains can provide an exquisite spatiotemporal regulation of Ca(2+)-mediated cellular function. Thus in this review we discuss PM lipid rafts and caveolae as Ca(2+)-signaling microdomains and highlight their importance in organizing and regulating SOCE channels.