The degenerin channels, epithelial sodium channels, and acid-sensing ion channels (DEG/ENaC/ASICs) play important roles in sensing mechanical stimuli, regulating salt homeostasis, or responding to acidification in the nervous system. They share a common topology with two transmembrane domains separated by a large extracellular domain and are believed to assemble as homomeric or heteromeric trimers into non-voltage gated, sodium-selective, and amiloride-sensitive ion channels. Amiloride is not the only drug that targets DEG/ENaC/ASICs, however, they are also emerging as a target of nonsteroidal anti-inflammatory drugs (NSAIDs) as well as other classes of small molecules. C. elegans has about 30 genes encoding DEG/ENaC/ASIC subunits and thus offers an excellent opportunity to examine variations in sensitivity to small molecules and biophysical properties. Here, we analyzed a subset of the C. elegans DEG/ENaC/ASIC proteins in order to test the hypothesis that individual family members have distinct properties. Toward this goal, we expressed five C. elegansisoforms in Xenopus laevis oocytes (DEGT-1d, DEL-1d, UNC-8d, MEC-10d and MEC-4d) and measured current amplitude, selectivity among monovalent cations, sensitivity to amiloride and its analogs, and sensitivity to NSAIDs. Of these five proteins, only DEGT-1d, UNC-8d, and MEC-4d form homomeric channels. Unlike MEC-4d and UNC-8d, DEGT-1d channels were insensitive to amiloride and its analogs and more permeable to K+ than to Na+. As reported for rat ASIC1a, NSAIDs inhibit DEGT-1d and UNC-8d. Unexpectedly, MEC-4d was strongly potentiated by NSAIDs, an effect that was decreased by mutations in the extracellular domain that affect inhibition of rat ASIC1a. Collectively, these findings reveal that not all DEG/ENaC/ASIC channels are amiloride-sensitive and sodium-selective and that NSAIDs can both inhibit and potentiate these channels.