Our first attempt resulted in transgene inactivation, most likely by A3B selecting against itself and promoting its own inactivation.15 Our second used the endogenous Rosa26 promoter to drive human A3B expression.16,41 This leads to modest A3B expression levels in most murine tissues, normal fertility, no overt cancer phenotypes, and subtle effects in lung-specific cancer models (without APOBEC signature mutations) in the presence of drug selection.16 Our third, reported here, leads to higher, human tumor-like levels of A3B in most murine tissues. The gene discussed is APOBEC3B; the disease is neoplasm.