The vast majority (~99%) of all known cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by naturally occurring mutations in two separate, but genetically interacting loci, pkd1 and pkd2. Pkd1 encodes a large multispanning membrane protein (PKD1) of an unknown function, while pkd2 encodes a protein (TRPP2, Polycystin-2, or PKD2) of the transient receptor potential (TRP) superfamily of ion channels. Biochemical, functional, and genetic studies support a model whereby PKD1 physically interacts with TRPP2 to form an ion channel complex that conveys extracellular stimuli to ionic currents. However, the molecular identity of these extracellular stimuli remains elusive. Functional studies in cell culture show that TRPP2 can be activated in response to mechanical cues (fluid shear stress) and/or receptor tyrosine kinase (RTK) and G protein couple receptor (GPCR) activation at the cell surface. Recent genetic studies in Chlamydomonas reinhardtii show that CrPKD2 functions in a pathway linking cell-cell adhesion and Ca²⁺ signaling. The mode of activation depends on protein-protein interactions with other channel subunits and auxiliary proteins. Therefore, understanding the mechanisms underlying the molecular make-up of TRPP2 containing complexes is critical in delineating the mechanisms of TRPP2 activation, and most importantly, the mechanisms by which naturally occurring mutations in pkd1 or pkd2 lead not only to ADPKD, but also to other defects reported in model organisms lacking functional TRPP2. This review will focus on the molecular assembly, function, and regulation of TRPP2 as a cell surface cation channel and discuss its potential role in Ca2+ signaling and ADPKD pathophysiology.