Pentameric ligand-gated ion channels (pLGICs, also known as Cys-loop receptors) are a large family of ion channels expressed in all Bilateria and in several groups of bacteria and archaea. They are activated by small-molecule neurotransmitters to mediate fast neurotransmission at many central and peripheral synapses and are the target of several drugs and insecticides. Here we review recent advances in the field, focussing on new insights on the structure of the agonist-binding site and on newly discovered protein–protein interactions involving pLGICs.