Subacute sclerosing panencephalitis (SSPE) is a chronic neurodegenerative disease of the central nervous system (CNS) that afflicts eight to 20 individuals per one million of those who become infected with measles virus (MV). The six cardinal elements of SSPE are: (1) progressive fatal CNS disease developing several years after MV infection begins; (2) replication of MV in neurons; (3) defective nonreplicating MV in the CNS that is recoverable by co-cultivation with permissive tissue culture cells; (4) biased hypermutation of the MV recovered from the CNS with massive A to G (U to C) base changes primarily in the M gene of the virus; (5) high titers of antibody to MV; and (6) infiltration of B and T cells into the CNS. All these parameters can be mimicked in a transgenic (tg) mouse model that expresses the MV receptor, thus enabling infection of a usually uninfectable mouse in which the immune system is or is not manipulated. Utilization and analysis of such mice have illuminated how chronic measles virus infection of neurons can be initiated and maintained, leading to the SSPE phenotype. Further, an active role in prolonging MV replication while inhibiting its spread in the CNS can be mapped to a direct affect of the biased hypermutations (A to G changes) of the MV M gene in vivo.