Macrocycles are large ring structures found in a wide variety of bioactive natural products. The macrocyclic constraint is a key structural element that orients functional groups in three-dimensional space for presentation to binding sites on biological targets. This conformational restriction has also been associated with increased binding affinity and oral bioavailability compared to corresponding linear structures. Accordingly, macrocycles are attractive targets in the diversity-oriented synthesis of natural product-based libraries for probe and drug discovery screening. However, macrocycles have been severely underutilized in this regard as efficient access to diverse collections of macrocyclic scaffolds has been hampered by challenges associated with traditional macrocyclization reactions. To address this problem, we have developed a concise, modular approach to the diversity-oriented synthesis of macrolactones and macrolactams using the oxidative cleavage of a bridging bond in polycyclic enol ethers and enamines. These substrates are assembled in only four or five synthetic steps and undergo ring expansion to afford highly functionalized macrocycles bearing handles for further diversification. In contrast to macrocyclization reactions of corresponding linear seco -acids, the ring expansion reactions are efficient and insensitive to ring size and stereochemistry, overcoming key limitations of conventional approaches to systematic macrocycle synthesis. Cheminformatic analyses of our macrocycle scaffolds indicate that these molecules access underrepresented regions of chemical space that overlap with natural products, including known macrolactones and macrolactams, and are complementary to those addressed by existing synthetic drugs and drug-like libraries. Efficient access to diverse collections of macrocycles is hoped to facilitate the continued evaluation of this important class of molecules in addressing challenging biological targets.