Activation of the inflammasome is involved in the progression of retinal degenerative diseases, in particular, in the pathogenesis of Age-Related Macular Degeneration (AMD), with NLRP3 activation the focus of many investigations. In this study, we used genetic and pharmacological approaches to explore the role of the inflammasome in a mouse model of retinal degeneration. We identify that Casp1/11 −/− mice have better-preserved retinal function, reduced inflammation and increased photoreceptor survivability. While Nlrp3 −/− mice display some level of preservation of retinal function compared to controls, pharmacological inhibition of NLRP3 did not protect against photoreceptor cell death. Further, Aim2 −/− , Nlrc4 −/− , Asc −/− , and Casp11 −/− mice show no substantial retinal protection. We propose that CASP-1-associated photoreceptor cell death occurs largely independently of NLRP3 and other established inflammasome sensor proteins, or that inhibition of a single sensor is not sufficient to repress the inflammatory cascade. Therapeutic targeting of CASP-1 may offer a more promising avenue to delay the progression of retinal degenerations. Age-Related Macular Degeneration (AMD) is a chronic inflammatory disease that is characterised by central vision loss due to retinal pigmented epithelium (RPE) and photoreceptor cell death in the macular region of the retina 1,2. While environmental, lifestyle and genetic risk factors are well established 2-4 , it is increasingly clear that central to disease progression is the accumulation of oxidative stress 5 and inflammation 6. A central component of inflammation is the inflammasome, multi-protein oligomers which form part of the innate immune system, acting in the first line of defence, sensing pathogen-derived or danger signals from pathogen invasion, or cellular stress signals including extracellular ATP or host dsDNA 1,7-9. Inflammasomes are composed of a pattern recognition receptor (PRR) sensor protein, including NACHT, LRR and PYD domains-containing protein 1 (NLRP1), NLRP3, NAIP-NLRC4, Absent in Melanoma 2 (AIM2), and Pyrin. Following activation, these sensor proteins form a complex with the adaptor protein Apoptosis-associated speck-like protein containing a CARD (ASC, or PYCARD) and protease enzyme Caspase-1 (CASP-1) 10,11. Activated CASP-1 in turn, cleaves and activates pro-inflammatory cytokines including interleukin-1β (IL-1β), large amounts of which are known to cause microglial activation and macrophage recruitment from the periphery, and ultimately photoreceptor cell death, characteristic features of AMD pathogenesis 3,8,12-16. Inhibition of IL-1β has been shown to reduce inflammation and further cell death 14 , highlighting the key role of the inflammasome in the progression of retinal degenerative diseases such as AMD.