Mutations in polycystin-2 (PC2) lead to autosomal dominant polycystic kidney disease (ADPKD). The molecular mechanism linking mutations in PC2 and the pathogenesis of ADPKD is not well understood. Therefore, understanding the functional regulation of PC2 and its interaction with other proteins under both physiological and pathogenic conditions is important for elucidating the disease mechanism and identifying potential molecular targets for treatment. Normally, PC2 functions as a calcium-permeable channel whose activity is regulated by calcium binding to the C-terminal domain of PC2 (PC2 Cterm). The PC2 Cterm is also involved in the PC2 channel assembly and hetero-oligomerization with other binding partners in cells. Different functional domains of the PC2 Cterm have been studied using structural approaches. Within the PC2 Cterm, there is a calcium-binding EF-hand domain, crucial for the calcium-dependent activity of the PC2 channel. Downstream of the EF-hand domain lies a coiled-coil region, which is involved in the assembly and hetero-interaction of the PC2 protein. The PC2 Cterm can form an oligomer, mediated by the coiled-coil region. Although PC2 Cterm has been extensively studied for its relationship with ADPKD and its importance in PC2 regulation, there are misunderstandings with respect to the definition of the domain topology within the PC2 Cterm and the functional role of each domain. Here, we review previous studies that connect the molecular properties of the domains of PC2 Cterm to distinct aspects of PC2 functions and regulation.