The art of natural product total synthesis is closely associated with two major determinants: the development/application of novel chemical reactions and the innovation in strategic use of classic organic reactions. While purposely seeking/applying a new synthetic methodology allowing nonconventional bond disconnections could shorten the synthetic route, the development of domino processes composed of a series of well-established reactions could also lead to a concise, practical, and aesthetically appealing synthesis. As an important class of textbook reactions, the 1,2-anionotropic rearrangements discovered at the dawn of modern organic chemistry have important bearings not only on chemical synthesis but also on the conceptual breakthroughs in the field. In its basic form, the 1,2-shift affords nothing but a constitutional isomer of the starting material and is therefore not a complexity-generating transformation. However, such a simple 1,2-shift could in fact change the molecular topology if the precursor is cleverly designed. More dramatically, it can metamorphosize the structure of the substrate when it is combined with other transformations in a domino sequence. In this Outlook, we highlight recent examples of natural product synthesis featuring a key domino process incorporating a 1,2-anionotropic rearrangement. Specifically, domino reactions integrating Wagner−Meerwein, pinacol, α-ketol, α-aminoketone, α-iminol, or benzilic acid rearrangements will be discussed.