This article provides a broad overview of the significant roles that morphophysiologic analyses of organotypic cultures of neural tissues explanted in vitro-initiated during the 1950s-have played in stimulating the more recent development of techniques for transplantation of neural cells and tissues into specific regions of the central nervous system (CNS) in vivo. The demonstrations by Crain and co-workers in the 1950s and 1960s that fetal rodent and human CNS neurons can continue to develop a remarkable degree of mature structure and function during many months of complete isolation in culture provided crucial evidence that development of many organotypic properties of nerve cells is regulated by epigenetic factors that ensure rather stereotyped expression despite wide variations in environmental conditions. These in vitro studies strongly suggested that fetal neural cells should, indeed, be capable of even more highly organotypic development after transplantation in vivo, as has been elegantly demonstrated by many of the successful CNS transplantation studies reviewed here.