Despite significant advances in NMR spectroscopy, structure elucidation of natural products, especially stereochemically complex polyketides with limited availability, is still a challenging task for chemists. Recent examples of structure determination, correction and disproof of structurally complex marine polyketide macrolides by chemical synthesis, namely lobatamide C, reidispongiolide A, callyspongiolide, palmerolide A, muironolide A, iriomoteolide-2a, and chagosensine cases, are summarized in this review, which highlights the scope and limitation of current NMR-based structure analysis and the vital role of chemical synthesis in structure elucidation.