Natural products continue to inspire and serve as the basis of new medicines. They also provide intricate problems that expose limitations in the strategies and methods employed in chemical synthesis. Several strategies and methods that have been developed in our laboratory and applied to the syntheses of architecturally complex natural products will be discussed. In particular, new ways to employ the cleavage of core bonds such as C–C and C–N bonds (i.e., break-it-to-make-it strategies) to achieve skeletal editing will be presented.