Transient receptor potential canonical (TRPC) proteins were identified as molecular candidates of receptor- and/or store-operated channels because of their close homology to the Drosophila TRP and TRPL. Functional studies have revealed that TRPC channels play an integrated part of phospholipase C-transduced cell signaling, mediating the influx of both Ca and Na into cells. As a consequence, the TRPC channels have diverse functional roles in different cell types, including metabotropic receptor-evoked membrane depolarization and intracellular Ca concentration elevation. Depending on the cellular environment and the protein partners present in the channel complex, the TRPC channels display different biophysical properties and mechanisms of regulation, including but not limited to the Ca filling state of the endoplasmic reticulum. Despite the overwhelming focus on STIM-regulated Orai channels for store-operated Ca entry, evidence is growing for STIM-operated TRPC channel activities in various cell types, demonstrating both store-dependent and store-independent mechanisms of TRPC channel gating. The existence of physical and functional interactions between plasma membrane-localized TRPC channels and other proteins involved in sensing and regulating the intracellular Ca store contents, such as inositol trisphosphate receptors, Junctate, and Homer, further argues for the role of TRPC proteins in linking plasma membrane ion transport with intracellular Ca stores. The interplay among these proteins will likely define the functional significance of TRPC channel activation in different cellular contexts and under different modes of stimulations.