Orexins (OX-A, OX-B) are involved in the regulation of sleep, feeding and reward. The action of these peptides is governed by Orexin Receptors 1 and 2 (OX1R, OX2R). In aim to understand the mechanisms involved upon activation of these receptors, we have identified the dynein light chains 1 and 3 (Dynlt1/3) as novel partners. We hypothesize that Dynlt1/3 are important for orexin receptor intracellular regulation. After identification of a strong interaction between OX1R and Dynlt1 and the importance of the OX1R C-terminal domain residues, the functional implication of this novel interaction was assessed. Ligand-induced internalization of OX1R was not altered by modification of Dynlt1/3 expression, yet its transit in early endosomes was accelerated by Dynlt1 over-expression. In conclusion, these data suggest that Dynlt1 promotes the exit of OX1R from early endosomes following ligand-induced internalization, in association with an accelerated signal termination as measured by the phosphorylation levels of ERK1/2.