Nuclear receptors control gene expression by recruiting transcriptional coactivators (or corepressors). The coactivators are master regulators that coordinately activate multiple distinct transcription factors and target genes and pathways to control major physiologic processes such as reproduction, inflammation, metabolism and growth. Because of their central role as nodes of regulation, coactivators are major targets in the development of numerous inherited and acquired endocrine-related pathologies such as infertility, endometriosis, disorders of carbohydrate, lipid and protein metabolism, and numerous cancers. Metabolism and growth are especially prominent pathways for coordinate regulation by coactivators such as SRC-2 and SRC-3. The pleiotropic functions of coactivators in pathways are the result of combinatorial posttranslational modifications of the proteins via enzyme cascades, in conjunction with certain biological isoforms of the proteins. In metabolic diseases and cancers, the intracellular concentrations and the PTM-directed activities of the coactivator proteins are critical for driving the transcription-dependent physiological outcomes, However, in the case of the cancer cells motility or in endometriosis, it is the coactivator proteins isoforms that are the major mediators of the disease progression. Thus, as a class, the coactivator proteins provide important insights to polygenic diseases. They also may represent new first-in-class types of potential targets for therapeutic intervention.