The protein variously called calsenilin, DREAM, or KChIP3 has been independently discovered three times, accounting for the three different names currently in use. Calsenilin appears to have three, perhaps independent, roles. Calsenilin binds and modulates some of the effects of the Alzheimer disease-related protein presenilin, while presenilin can modulate some of the effects of calsenilin. Calsenilin binds the dynorphin response element and regulates dynorphin expression, hence regulating nociception. Calsenilin binds Kv channels and modulates potassium conductance, playing a role in long-term potentiation as well as in other important plastic pathways. Other members of the calsenilin family share at least some of the roles. For example, KChIP1, KChIP2, and CALP can all bind presenilins and can all modulate A-type potassium channels. Further functional dissection of this family of proteins will provide insight into numerous aspects of neuronal function and will illuminate the role of the calsenilin family of proteins in disease.