The Nuclear Hormone Receptor (NHR) superfamily of transcription factors mediate signaling by a diverse array of vitamins, hormones, and small molecules to regulate the expression of specific target genes involved in many important biological functions, such as development, metabolism, homeostasis, cell growth and differentiation, and others. NHRs regulate gene expression in coordination with an increasing number of coregulators (corepressors and coactivators). Many NHRs are involved in a variety of human diseases, including cancer. Thus ligands of RAR/RXRs (retinoids), steroid receptors (ER, AR), PPARs and others have been pursued as novel targeted therapies for the chemoprevention and treatment of cancers, including prostate, breast, lung, colon cancers as well as hematologic malignancies. Dr. Piedrafita has been working for the last decade on the mechanism of action of a family of synthetic retinoids called retinoid-related molecules (RRMs) or adamantly arotinoids (AdArs) that show strong anticancer activity. This lead to the discovery that certain AdArs induced tumor cell apoptosis independently of RAR/RXR activity, but rather by inhibiting protein kinases that are often hyperactivated in cancer, such as IKK-2. Given the RAR-mediated toxicity of classical retinoids, research is now focused in optimizing lead AdArs to eliminate RAR activity while enhancing IKK-2 inhibitory activity. Most recently, Dr. Piedrafita’s interest has been expanded to the identification and characterization of novel ligands of orphan receptors and other NHRs with strong connection in cancer.