Abstract: The ligand-gated chloride channels (LGCCs) are part of the cysteine loop ligand-gated ion channels (Cys-Loop LGICs) superfamily in insects. The most remarkable characteristic of the Cys-Loop LGICs is that they possess a Cys-Loop motif consisting of two cysteines separated by 13 amino acid residues in the N-terminal extracellular domain. Members of the LGCCs including glutamate-gated chloride channels (GluCl), histamine-gated chloride channels (HACls) and pH-sensitive chloride channels (pHCls) are specifically expressed in insects. There have been many reviews on GluCl, and in this review, we focus on HACls and pHCls. The HACls and pHCls were only found in invertebrates and could be ideal targets for the development of novel insecticides with high selectivity. However, only the avermectins insecticides are capable of non-specific binding of HACls and pHCls. There are generally two genes coding for HACls and 1-5 genes coding for pHCls with various alternative splicing in insects. In addition to being activated by the endogenous agonist histamine, HACls can also be activated by high concentrations of γ-aminobutyric acid. The pHCls produce progressively increasing currents in response to elevated extracellular pH, as well as concentration-dependent currents in response to zinc ion. Both HACls and pHCls play various important physiological functions in insects, of which HACls are involved in light reception, color processing and temperature preference; whereas pHCls are related to fluid secretion, nutrient intake and alkaline taste sensation. In this review, we describe the discovery, subunit profile, pharmacological properties and physiological functions of HACls and pHCls, which would provide novel target for the development of highly selective insecticides.