Total synthesis of englerin A, a recently reported sesquiterpenoid exhibiting potent and selective growth inhibition against renal cancer cell lines, has been accomplished. The successful strategy featured a [5 + 2] cycloaddition reaction to cast the seven-membered oxabicyclic key intermediate in both racemic and optically active forms. Synthetic (+/-)-englerin A, (+/-)-englerin B, (+/-)-englerin B acetate, a hydroxy acetate, a tert-butyldimethylsilyl ether, and hydrogenated (+/-)-englerin A (31) were tested for their cytotoxicity against a selected panel of cancer cell lines, and the results are path-pointing to more focused structure-activity relationship studies.