A convergent and enantioselective total synthesis of (-)-amphidinolide O (1) and P (2), 15-membered macrolides with seven chiral centers along with many functional groups, is described. The key reactions include enantioselective Brown allylation, anti- and syn-selective aldol reactions, (E)-selective olefin metathesis, conformation-controlled stereoselective epoxidation, and selective introduction of the exomethylene group. Assignments of the absolute stereochemistries of the natural (+)-amphidinolide O (ent-1) and P (ent-2) are also discussed in detail.