A particularly intriguing aspect of the dengue viruses is the extraordinary extent to which they acquire a predilection for growth in the central nervous system (CNS) after “adaptation” to the mouse. Studies to be summarized in this section show that the acquisition of this trait is a process probably involving more than one mutational and selective step. It manifests itself, first, in the ability of the virus to grow in, and produce disease referable to, the CNS of newborn mice; second, in the gradual emergence of a similar capacity for growth and pathological effects in adult mice. Coincident with the first step is the diminution of pathogenicity for man (attenuation), while the stabilization of neurovirulence for the mouse in the second phase seems to be associated with the ability of the virus to grow in the CNS of other hosts, viz., the monkey and the chick embryo. That the transition from the first to the second phase involves a modification in the viral genome is suggested by previously unpublished results which will be presented below. It is implicit in this statement that these studies were concerned with the behavior of populations of heterogeneous viral particles, not of cloned stocks. It should be noted at the outset that this approach suffers from the lack of clearly defined multiple genetic markers and test systems and that the results merely illustrate the need for systematic genetic studies on dengue viruses.