Biological control of key processes, such as development and reproduction, is largely ascribed to a superfamily of ligand-dependent and independent transcription factors named Nuclear Receptors (NRs). Given their ability to accommodate ligands, NRs are prime targets of man-made compounds that mimic or antagonise the action of endogenous ligands. Accordingly, NRs occupy a prominent role in OECD and EPA guidelines for testing and assessment of Endocrine disrupting chemicals (EDCs). Although NR assays are already a key instrument in the OECD Conceptual Framework for Testing and Assessment of EDCs, the focus is mostly on vertebrate NRs. Here, we address the chief knowledge gaps in the field. More specifically, we (1) verify the growing availability of genomes/transcriptome projects, (2) highlight gaps in the identification and characterization of metazoan NR and in the establishment of (3) life cycle and (4) toxicity testing protocols. An overall bias towards vertebrates and selected invertebrate groups, notably Arthropoda, Annelida and Mollusca, was observed. Hence, if we aim to improve risk assessment of EDCs and emerging pollutants at an ecosystems scale, and understand their mode of action (MOA), we must establish a framework to include a broad phylogenetic sampling of Metazoans.