The first asymmetric synthesis of the polyether antibiotic lonomycin has been achieved. The skeleton is assembled through the synthesis and union of two subunits comprising the C-1-C-11 and C-12-C-30 portions of the structure. These fragments were constructed utilizing auxiliary-based asymmetric aldol and acylation reactions to control the absolute stereochemical relationships in the structure. The majority of the 1,2-dioxygen relationships in the polyether portion of the molecule were established through a succession of epoxidation reactions which were transformed through intramolecular heterocyclization to establish rings D, E, and F. The major subunits were coupled through a highly diastereoselective aldol reaction to construct the C-11-C-12 bond. Spiroketalization followed by selective methylation of the C-11 hydroxyl provided the protected ionophore in high yield.