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Cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 account for >70% of all known cases of achromatopsia. Cones degenerate in achromatopsia patients and in CNGA3^−/− and CNGB3^−/− mice. This work investigates the molecular basis of cone degeneration in CNG channel deficiency. As cones comprise only 2–3% of the total photoreceptor population in the wild-type mouse retina, we generated mouse lines with CNG channel deficiency on a cone-dominant background, i.e. CNGA3^−/−/Nrl^−/− and CNGB3^−/−/Nrl^−/− mice. The retinal phenotype and potential cell death pathways were examined by functional, biochemical, and immunohistochemical approaches. CNGA3^−/−/Nrl^−/− and CNGB3^−/−/Nrl^−/− mice showed impaired cone function, opsin mislocalization, and cone degeneration similar to that in the single knock-out …