Molecular rearrangements are a powerful tool for constructing complex structures in an atom- and step-economic manner, translating multistep transformations into an intrinsically more sustainable process. Mechanochemical molecular rearrangements become an even more appealing eco-friendly synthetic approach, especially for preparing active pharmaceutical ingredients (APIs) and natural products. Still in their infancy, rearrangements promoted by mechanochemistry represent a promising approach for chemists to merge molecular diversity and green chemistry perspectives toward more selective and efficient syntheses with a reduced environmental footprint.