Brevenal is a polyether natural product isolated from laboratory cultures of the Florida red tide-forming dinoflagellate, Karenia Brevis. Its gross structure, including relative stereochemistry, was disclosed based on extensive 2D NMR studies. It has been reported that brevenal competitively displaces tritiated dihydrobrevetoxin from voltage-sensitive Na^+ channels and acts as a natural brevetoxin antagonist in vivo. More importantly, brevenal improved tracheal mucus velocity in picomolar concentrations in an animal model of asthma. Thus, it may be a source of novel therapeutic agents for treatment of cystic fibrosis and other respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). Intrigued by these biological profiles of brevenal, we embarked on the total synthesis of brevenal by means of our developed convergent methodology. Suzuki-Miyaura coupling of the AB ring enol phosphate 6 and an alkylborane derived from the DE ring exo-olefin 7 proceeded smoothly to afford coupling product 23. The C ring was then constructed by mixed-thioacetalization followed by one-pot oxidation/methylation. After construction of the left-hand (E,E)-diene side chain by means of CuTC-mediated Stille coupling, the total synthesis was completed by installing the right-hand (Z)-diene chain via Wittig reaction. However, ^1H and ^<13>C NMR spectra of synthetic 1 were not identical with those of the natural product. Detailed NMR studies suggested that the true structure of brevenal is the C26-epimer of the originally proposed structure. This notion is also supported by the postulated biosynthetic pathway of marine polyether natural products. In the event, this proved to be correct as the spectroscopic data of synthetic 2 were completely identical with those of the natural product. In addition, the optical rotation of synthetic 2 matched the value for the natural product. Thus, we succeeded in unambiguous determination of the absolute configuration of brevenal through our total synthesis endeavor.