SLC18A2 encodes the vesicular monoamine transporter 2 protein that regulates neurotransmission and reduces cytosolic toxicity of monoamines. Deletion of this gene causes lethality in mice, and DNA sequence variation in this gene is associated with alcoholism and Parkinson's disease, among other disorders. The Caucasian SLC18A2 promoter has at least 20 haplotypes (A-T), with A representing two-thirds of 1460 chromosomes. It is not known why A is selected in the human lineage. To understand the selection, here we took a functional approach by investigating the regulations of 4 representative haplotypes (A, C, G, and T) by 17 agents. We show that 76.5% of the agents were able to regulate A but only 11.8-23.5% of them regulated the 3 other infrequent ones, observing a positive correlation between haplotype frequency and regulatability. Pathway and molecular analyses revealed five signaling hubs that regulate the four haplotypes differentially, probably through targeting the polymorphic core promoter region. These findings suggest that greater diversity of transcriptional regulations is the driving force for the haplotype selection in SLC18A2.