This chapter provides a history of how apoptosis‐inducing ligands for the orphan nuclear receptor small or short heterodimer partner (SHP, NR0B2) were derived from the RAR‐selective synthetic retinoid 6‐[3'‐(1‐adamantyl)‐ 4'‐hydroxyphenyl]‐2‐naphthalenecarboxylic acid (AHPN, also called CD437) by removing structural features that favored interaction with the retinoic acid receptors (RARs) and adding those that disfavored them. The members of the steroid/thyroid hormone receptor superfamily or nuclear receptors (NRs) are a group of related proteins generally having six major domains, of which the fifth (E) is termed the ligand‐binding domain (LBD), regardless of whether or not an endogenous small‐molecule ligand has been identified. Examination of LBD sequences indicates either high identity and/or homology among the NRs, which form a basis for their classification into particular families and subfamilies. Binding nonspecificity or cross‐reactivity of NR ligands can become problematic when high concentrations are used experimentally.