Nuclear receptors (NRs) are intracellular proteins that provide the fundamental link between circulating hormones and local tissue responses. They thereby represent some of the most promising pharmacological targets for the treatment of disease, including many types of cancers, autoimmune diseases and metabolic syndromes. While NRs primarily control gene expression in the nucleus, some have been found to activate signaling pathways in other parts of the cell (non-genomic). These non-genomic pathways are fast-acting and can affect important cellular processes directly or feedback to mediate the effects of other nuclear receptors. It is therefore likely that they fulfill roles in both normal physiology and disease. In this project, I will use advanced proteomic methods to explore the two members of the NR subfamily 1 group D (the Rev-erbs), which regulate crucial components of metabolism, development and daily rhythm. Early evidence from the Krause lab shows that these NRs associate with a number of intracellular motor proteins, which relocate them to distinct cytoplasmic regions such as neuronal processes. This translocation indicates that the Rev-erbs have important functions in addition to their direct role in gene expression. I will identify this pathway by comprehensively determining Rev-erb-interacting cytoplasmic complexes, then use intracellular localization techniques and experimental treatments to determine its functional importance. The ubiquitous nature of these NR-binding sites on motor proteins means that the general mechanism(s) identified here likely represent a widespread phenomenon. By exploring Rev-erb transport, I will develop a better understanding of the link between Rev-erbs and similar localization of fragment X mental retardation protein (FMRP). Finally, crosstalk between the Rev-erbs and other NRs could help develop therapies that directly target features of NR-signaling without compromising entire pathways.