Members of the leucine-rich repeat-containing 8 (LRRC8) protein family, composed of the five LRRC8A-E isoforms, are pore-forming components of the volume-regulated anion channel (VRAC). LRRC8A and at least one of the other LRRC8 isoforms assemble into heteromers to generate VRAC transport activities. Among the five LRRC8 isoforms, the LRRC8D isoform is the largest one owing to a long first extracellular loop between the transmembrane (TM) 1 and 2 helices. When incorporated into LRRC8 hetero-hexamers, the LRRC8D isoform facilitates the permeation of uncharged substrates such as taurine and GABA, negatively charged glutamate, and even positively charged lysine. Moreover, LRRC8D-containing hetero-hexamers facilitate the uptake of the antibiotic blasticidin S and the Pt-based anticancer drug cisplatin, resulting in cancer drug resistance in patients with down-regulated LRRC8D isoforms.