Comparative genomics seeks to determine which DNA sequences are most likely to be functional and to predict what those functions may be. Interspecies alignments provide the foundation for this task, but they are not sufficient. Comparisons among placental mammals appear to be “too close” for some purposes, revealing a mix of functional and apparently neutral sequences, while comparisons between mammals and birds or fish can miss many functional sequences. More closely related species (e.g. among primates) can reveal evidence of adaptive evolution (positive selection). Talks in this session will discuss the partitioning of genome sequences both by composition (isochores and bands, Bernardi) and by differences in conservation (Sakate), and describe the new mouse reference sequence (Church). Alignments in closely related primates are used to learn more about promoters(Querfurth) and gene families (Hallast). Comparative approaches are also used to deepen our understanding of the evolution of imprinting (Edwards), to better understand associations of polymorphism with heart disease (Sandling), and to predict and validate cis-regulatory modules in mammals (Hardison).