In the last decade, the claudin family of integral membrane proteins has been identified as the major protein component of the tight junctions in all vertebrates. The claudin superfamily proteins also function to regulate channel activity, intercellular signaling, and cell morphology. Subsequently, claudin homologues have been identified in invertebrates, including Drosophila and Caenorhabditis elegans. Recent studies demonstrate that the C. elegans claudins, clc-1 to clc-5, and similar proteins in the greater PMP22/EMP/claudin/calcium channel γ subunit family, including nsy-1-nsy-4 and vab-9, while highly divergent at a sequence level from each other and from the vertebrate claudins, in some cases play roles similar to those traditionally assigned to their vertebrate homologues. These include regulating cell adhesion and passage of small molecules through the paracellular space. The claudin superfamily proteins also function to regulate channel activity, intercellular signaling, and cell morphology. Study of claudin superfamily proteins in C. elegans should continue to provide clues as to how core claudin protein function can be modified to serve various specific roles at regions of cell-cell contact in metazoans.