The enantioselective total synthesis of the potent antiparasitic agent milbemycin D (1) has been achieved. The spiroketal fragment is prepared through a novel spiroketalization of a hydroxy pyrone to set the anomeric stereocenter and establish functionality for the stereocontrolled attachment and subsequent extension of the connecting chain between the spiroketal and the hexahydrobenzofuran fragment. The hexahydrobenzofuran fragment is constructed through the exploitation of a sequential electrophilic cyclization-[2,3]-sigmatropic rearrangement to close the oxygen-containing ring and incorporate the C5 hydroxyl. A lithium bromide accelerated Wittig olefination joins the spiroketal-containing subunit and the hexahydrobenzofuran subunit at the C10,11 double bond in high yield. Subsequent oxidation of the C1 hydroxyl provides access to the seco acid, which smoothly undergoes macrolactonization. The sensitive C2 stereochemistry and the C3,4 double bond are incorporated without epimerization at C2 or migration of the C3,4 double bond.