“Inhibition of Cell Proliferation through Regulated Intramembrane Proteolysis of CREB3L1” guides the reader though the discovery of CREB3L1 as a membrane-bound transcription factor that prevents the proliferation of virus-infected cells. Upon activation, CREB3L1 is found to block the proliferation of cells infected with diverse DNA and RNA viruses, including murine gamma-herpesvirus 68, HCV, West Nile virus, and Sendai virus. The reader is then lead through the discovery that doxorubicin, a widely used anti-cancer drug, requires CREB3L1 to perform the anti-proliferative function utilized in cancer therapy. Data is presented that doxorubicin stimulates de novo synthesis of ceramide, which in turn activates the regulated intramembrane proteolysis of CREB3L1. This leads to the transcription of anti-proliferative genes that block tumor cell proliferation.