The archazolids are complex polyketides isolated from the myxobacterium Archangium gephyra and are potent inhibitors of vacuolar type ATPases. Herein, we report the first total synthesis of archazolid A, which establishes unequivocally the relative and absolute configuration of this macrolide antibiotic. Key features of our synthesis include an aldol condensation for construction of the delicate (Z,Z,E)-triene-system, an E-selective Heck reaction on a highly elaborate substrate, and a HWE macrocyclization to close the 24-membered macrolactone.