Three fundamental issues in postgenomic biology are (i) how the amino acid sequence of a given human protein predicates its structure, function, and regulation; (ii) how a protein is compared to its paralogs, as well as to its orthologs and other homologous proteins in model organisms; and (iii) how related studies contribute to the understanding of human pathology and the development of efficacious diagnostic and therapeutic means. These fascinating issues have inspired us to conduct a comprehensive analysis of information available on class II histone deacetylases (HDACs). In what follows, we will start with a brief description of different classes of HDACs and then compare class II HDACs from yeast and higher organisms in terms of domain organization, function, and regulation. We will also discuss evidence that links class II human HDACs to cardiomyopathy, osteodystrophy, neurodegenerative disorders, and cancer and will propose that, in addition to inhibitors, activators of these HDACs are of potential therapeutic value.