The precise sequence of molecular events underlying release of neurotransmitter in neurons is yet to be fully understood. This process, called exocytosis, is tightly controlled by a number of protein-protein and protein-lipid interactions. One such regulatory factor is Munc18a, a cytosolic protein characterized by its interaction with the molecular machinery of exocytosis, primarily with the target SNARE protein, syntaxin I a. While Munc18a interactions have been extensively investigated for more than a decade, the role of Munc18a in vesicular fusion is still not fully defined. In this review, we discuss: (i) the recent analysis of the role of Munc18a in tethering and docking, (ii) the known structural and (iii) functional data surrounding Munc18a interactions with numerous other proteins of the exocytic machinery. Integration of Munc18a regulation by phosphorylation and lipids and the apparent complexity of its pleiotropic functional interactions is critical to deciphering Munc18a's role in exocytosis. (c) 2006 Elsevier Ltd. All rights reserved.