Neurobeachin (Nbea) is implicated in vesicle trafficking in the regulatory secretory pathway, but details on its molecular function are currently unknown. We have used Drosophila melanogaster mutants for rugose (rg), the Drosophila homolog of Nbea, to further elucidate the function of this multidomain protein. Rg is expressed in a granular pattern reminiscent of the Golgi network in neuronal cell bodies and colocalizes with transgenic Nbea, suggesting a function in secretory regulation. In contrast to Nbea(-/-) mice, rg null mutants are viable and fertile and exhibit aberrant associative odor learning, changes in gross brain morphology, and synaptic architecture as determined at the larval neuromuscular junction. At the same time, basal synaptic transmission is essentially unaffected, suggesting that structural and functional aspects are separable. Rg phenotypes can be rescued by a Drosophila rg+ transgene, whereas a mouse Nbea transgene rescues aversive odor learning and synaptic architecture; it fails to rescue brain morphology and appetitive odor learning. This dissociation between the functional redundancy of either the mouse or the fly transgene suggests that their complex composition of numerous functional and highly conserved domains support independent functions. We propose that the detailed compendium of phenotypes exhibited by the Drosophila rg null mutant provided here will serve as a test bed for dissecting the different functional domains of BEACH (for beige and human Chediak-Higashi syndrome) proteins, such as Rugose, mouse Nbea, or Nbea orthologs in other species, such as human.