A combination of DIBAL-H and Cp2ZrCl2 is shown to promote the regioselective cleavage of primary acetates on a broad scope of substrates, ranging from carbohydrates to terpene derivatives, with a high tolerance toward protecting groups and numerous functionalities found in natural products and bioactive compounds. Apart from providing highly valuable building blocks in only two steps from biosourced raw materials, this selective de- O-acetylation should also be strongly helpful to solve selectivity issues in organic synthesis.