The REGγ proteasome has been reported as a shortcut to destruction of proteins. However, the physiological functions of REGγ are largely unknown. To understand the potential biological roles of REGγ associated with different tissues or cell types, we performed systematic analysis of REGγ gene expression in 20 different tissues from mice, followed by validation of protein expression in mouse tissues and bioinformatic analysis of REGγ gene expression profiles in selected human tissues. Comparative analysis of REGγ distribution in different tissues from wild-type and REGγ knockout mice indicates that REGγ is present in many tissues and is specifically expressed in some cell types. The highest expression of REGγ is in the testis and unique expression features of REGγ are revealed in a subset of neurons, including retinal ganglion cells and Purkinje cells. It is also expressed in reproductive and gastro-intestinal organs. These expressed patterns suggest potentially important functions for REGγ in the nervous system, reproductive system and in cells with proliferative capacity. Consistent with the importance of its expression in reproductive tissue, REGγ deficiency results in dose-dependent reduction in litter size.