Cystic fibrosis (CF) is the most common fatal genetic disorder of caucasians. While it has been hypothesized that there is a CF heterozygote advantage which allowed the gene to achieve such high prevalence, the nature of that advantage remains a mystery. The recent identification and sequencing of the CF gene has increased the probability that the CF heterozygote advantage will be discovered. In this hypothesis we review the information which is known about the selection of the CF mutation and its cellular consequences, and present evidence which suggests that resistance to cholera may have been the environmental factor which selected CF heterozygotes over their 'normal' homozygote cohort. Future lines of experimentation and possible clinical applicability to therapy of secretory diarrhea are presented.

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