The function and the organization of eukaryotic cells require directional transport of vesicles between compartments. This sort of membrane flow relies on the presence of docking and fusion machinery. The core of this machinery is a protein complex composed of syntaxin, SNAP-25 and VAMP, collectively termed SNAREs. A correct interaction among SNARE prototypes is essential for fruitful docking and fusion. Analysis of large-scale sequencing projects reveals that each of the SNARE proteins (syntaxin, SNAP-25 and VAMP) is a member of a large protein family that is represented in every eukaryotic genome. The diversity among the three SNARE prototypes allows an enriched combinatorial make-up to meet a wide range of cellular demands for secretion. Herein, we discuss the diversity in SNARE proteins from a genomic perspective. We combine information from large-scale sequence data with structural and functional classifications of SNAREs. Using a sequence-based automated protein classification tool, we expose weak but significant connections among all three SNARE protein clusters. These connections define a local evolutionary network within the protein universe. Genomic data allows us to identify classical SNAREs as well as their remote evolutionary relatives. We focus on the SNARE representatives from human and plant genomes to discuss the source of complexity and specificity for docking and fusion in a eukaryotic cell. How many of the potential SNARE combinations are indeed valid in vivo, and to what extent does each combination specify a biochemical and biophysical unique entity, is yet to be experimentally determined.