Retinal degenerations such as retinitis pigmentosa (RP) or glaucoma are a major cause of blindness in humans. Understanding the mechanisms underlying the various types of retinal degeneration is a pre-requisite for the development of rational therapies for these diseases. Activation of the calcium dependent protease, calpain, has been suggested to play an important role in cell death in various neuronal tissues including the retina. Improved detection and analysis of calpain activity during degenerative processes is likely to expand the list of pathological conditions with calpain involvement. We give a short overview of the methods available for the detection of calpain activity, and briefly discuss properties of calpain inhibitors. We then discuss the role of calpains in different cell death mechanisms and review existing work on retinal degeneration and the possible involvement of calpains therein. The implication of calpains in retinal cell death raises the possibility to use calpain inhibitors to prevent or delay retinal degeneration.